Combination of niraparib and abiraterone for treatment of metastatic castration-resistant prostate cancer

Abstract

The present disclosure relates to a pharmaceutical product having at least one batch indication, wherein the pharmaceutical product comprises niraparib and abiraterone acetate.

Description

[0001] A portion of the disclosure in this patent document includes copyrighted material. The copyright holder does not object to anyone reproducing this patent document or patent disclosure verbatim from the patent and trademark office patent documents or records, but otherwise retains all related copyrights. Technical Field

[0002] This disclosure relates to a method of treating metastatic castration-resistant prostate cancer (mCRPC) using an approved pharmaceutical product containing niraparib and abiraterone acetate. This disclosure also relates to an approved pharmaceutical product having at least one indication for the treatment of mCRPC. Methods of selling or providing a sold approved pharmaceutical product containing niraparib and abiraterone acetate, wherein the approved pharmaceutical product is approved for at least one indication, are also disclosed.

[0003] This disclosure relates to a method of treating metastatic castration-resistant prostate cancer (mCRPC) using a pharmaceutical product containing niraparib and abiraterone acetate. This disclosure also relates to a pharmaceutical product having at least one indication for the treatment of mCRPC. Methods of selling or providing a pharmaceutical product containing niraparib and abiraterone acetate, wherein the pharmaceutical product is approved for at least one indication, are also disclosed. Background Technology

[0004] Globally, prostate cancer is the second most common cancer among men and the fifth leading cause of cancer death, accounting for 1,400,000 (14.1%) new cancer cases and causing 375,304 (6.8%) cancer deaths in 2020.

[0005] While patients with localized prostate cancer can be cured with current therapies, the onset of metastasis signals a potentially fatal disease. Throughout the spectrum, prostate cancer growth and survival depend on androgen-mediated signaling. For decades, initial (first-line) treatment for metastatic prostate cancer has been surgical castration via bilateral orchiectomy or chemical castration using androgen deprivation therapy (ADT). ADT typically offers initial benefits; however, resistance to ADT inevitably develops.

[0006] In addition to androgen dependence, DNA repair abnormalities have been identified in approximately 25%–30% of patients with metastatic prostate cancer. Examples of these homologous recombination repair (HRR) gene alterations include those in the BRCA1, BRCA2, CDK12, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or ATM genes.

[0007] Several pieces of evidence suggest that HRR gene alterations act as a second oncogenic driver in patients with mCRPC, as demonstrated by worse tumor outcomes in these patients. Patients with both mCRPC and HRR gene alterations have a shorter life expectancy (median CSS of 23.3 months for mCRPC) compared to patients with mCRPC without HRR gene deficiency (median etiology-specific survival [CSS] of 33.2 months for mCRPC).

[0008] Clinical trials using poly(ADP-ribose) polymerase inhibitors (PARPi) are ongoing, but they are not without obstacles. For example, clinical trials using veliparib and pamipanib have been halted. This data clearly demonstrates that the search for safer and more effective treatments for mCRPC remains complex and unpredictable to date.

[0009] In the pharmaceutical industry, the path from drug discovery to approval is long and fraught with uncertainty. For prostate cancer products, the average time from Phase 1 clinical trials to approval is 9.3 years. To date, ClinicalTrials.gov alone has registered 5,927 prostate cancer clinical studies, and the probability of a prostate cancer product receiving regulatory approval from Phase 1 is less than 5%. The final path to approval is also not certain or inevitable, as failures continue to occur even up to Phase 3, with the average probability of a prostate cancer drug progressing from Phase 3 being only 50%. This is not only due to the highly unpredictable and uncertain nature of how pharmaceutical products will affect human biology, but also because how regulatory agencies interpret data and whether the data is sufficient to support the approval of investigational drugs for commercial use is often unpredictable human behavior.

[0010] The Magnitude study is a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of once-daily niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg plus prednisone 10 mg, versus placebo in patients with mCRPC (malignant cerebral palsy). The Magnitude study has been ongoing for several years, involving 318 study sites worldwide, and has enrolled 765 patients to date.

[0011] In the first interim analysis 1 (IA1), no adverse effect on overall survival (OS) was observed in patients with mCRPC and HRR alterations treated with niraparib plus AAP in cohort 1, with a hazard ratio (HR) of 0.938 and a 95% confidence interval (CI) of (0.648, 1.358), p = 0.7333. The significance threshold for OS in this first interim analysis was 0.0005. No median was reached in either treatment group. A pre-specified analysis of subjects with all HRR alterations except ATM alterations showed an OS HR of 0.910 and a 95% CI of (0.608, 1.362). Another pre-specified analysis of subjects with all HRR alterations but excluding ATM and CDK12 alterations showed a favorable OS HR of 0.883 and a 95% CI of (0.586, 1.330). OS analysis in the non-BRCA subgroup showed a HR of 0.917, 95% CI (0.547, 1.536), and nominal p = 0.7407; while OS analysis in the BRCA subgroup showed a HR of 0.961, 95% CI (0.565, 1.633), and nominal p = 0.8819.

[0012] Additional follow-up and further OS analysis are needed to understand the impact of individual genes and coexisting mutations.

[0013] At IA2, the hazard ratio (HR) for overall survival (OS) was 0.881 in the BRCA subgroup. The median OS for patients treated with niraparib plus AAP was 29.27 months (95% CI, 27.7, not estimable), while the median OS for patients treated with placebo plus AAP was 28.6 months (95% CI, 23.8, 32.95). Multivariate analysis considering baseline imbalances in patients indicated that niraparib plus AAP was associated with better survival (HR = 0.682; 95% CI: 0.445, 1.046). However, the data are still immature due to significant deletions at IA2.

[0014] Overall survival (OS) is typically defined as the average length of time a patient survives after starting treatment. OS is often considered the "gold standard" (or ideal) primary endpoint in oncology because cancer patients generally hope to take medications that help extend their lives. However, demonstrating OS advantage in clinical trials can be time-consuming, expensive, and challenging in other ways. Therefore, researchers use other clinical endpoints to demonstrate patient benefit, such as overall response rate and progression-free survival.

[0015] Therefore, overall survival data are needed to demonstrate the benefit of once-daily administration of niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg and prednisone 10 mg in patients with mCRPC who have HRR gene alterations.

[0016] Drug products that need approval would provide more effective and safer treatment options for patients with mCRPC who have HRR gene alterations, or overcome the potential treatment deficiencies of existing therapies.

[0017] There is a need for pharmaceutical products to provide more effective and safer treatment options for patients with mCRPC who have HRR gene alterations, or to overcome the potential treatment deficiencies of existing therapies.

[0018] This disclosure addresses these needs by demonstrating improved overall survival in the BRCA-mutated subgroup of mCRPC patients compared to OS data obtained in IA1 and IA2.

[0019] The disclosed approved drug products, the treatments using these approved drug products, and their medical uses are designed to meet these and other important needs.

[0020] The disclosed pharmaceutical products, the treatments using these pharmaceutical products, and their medical uses are designed to meet these and other important needs. Summary of the Invention

[0021] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product comprises niraparib and abiraterone acetate.

[0022] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product wherein the pharmaceutical product or approved pharmaceutical product is indicated in combination with prednisone for the treatment of patients who have been diagnosed with a harmful or suspected harmful breast cancer mutation (BRCAm) mCRPC by a test or approved test.

[0023] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product wherein, in patients with harmful or suspected harmful BRCAm mCRPC detected by a test or approved test, the pharmaceutical product or approved pharmaceutical product induces a median overall survival (OS) of 30.4 months with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

[0024] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product in which the median overall survival (OS) HR is 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis, which adjusts for external validation and clinically relevant baseline prognostic factors selected from prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, number of bone lesions, and visceral disease.

[0025] One object of the present invention is to provide a method for treating a patient with mCRPC who has been found to have a harmful or suspected harmful BRCAM by a test or approved test, the method comprising administering a pharmaceutical product or approved pharmaceutical product as defined herein in combination with prednisone to the patient.

[0026] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product as defined herein for use in a method for treating mCRPC patients with harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone.

[0027] One object of the present invention is to provide a pharmaceutical product or approved pharmaceutical product comprising niraparib and abiraterone acetate, used in combination with prednisone or prednisolone in a method of treating adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1 / 2 mutations (germline and / or somatic mutations) who are not clinically indicated for chemotherapy; wherein BRCA positive status is determined using a validated test method; wherein a single daily dose of the pharmaceutical product or approved pharmaceutical product is 200 mg niraparib and 1,000 mg abiraterone acetate, and a daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity occurs; characterized in that the treatment includes improving median overall survival (OS) to 30.4 months, with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120). Attached Figure Description

[0028] Figure 1 Kaplan-Meier plot of overall survival in BRCA+ patients (cohort 1), one group receiving niraparib and abiraterone acetate plus prednisone, and the other group receiving placebo and abiraterone acetate plus prednisone.

[0029] Figure 2 Forest plot of overall survival for subgroups defined by baseline clinical disease characteristics (cohort 1 BRCA) Figure 3aKaplan-Meier plot of time to symptom progression (TSP) in BRCA+ patients (cohort 1), one group receiving niraparib and abiraterone acetate plus prednisone, and the other group receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone experienced a delayed TSP. NE: Not estimable.

[0030] Figure 3b Kaplan-Meier plot of time to initiation of cytotoxic chemotherapy (TCC) in BRCA+ patients (cohort 1), one group receiving niraparib and abiraterone acetate plus prednisone, and the other group receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone had a delayed TCC. NE: Not estimable.

[0031] Figure 4 Kaplan-Meier plots of radiographic progression-free survival assessed by BICR in the BRCA population (MAGNITUDE, primary analysis) Figure 5 Kaplan-Meier plot of radiographic progression-free survival in BRCAM mCRPC patients in MAGNITUDE cohort 1, as reviewed by the center. Figure 6 Kaplan-Meier plots of radiographic progression-free survival assessed by BICR in the BRCam population (MAGNITUDE, primary analysis) Figure 7 Kaplan-Meier plot of overall survival in the BRCAm population (MAGNITUDE, final analysis) Figure 8 Application method: Press and hold. Figure 9 Application method. Pull out. Figure 10 Packaging instructions. Fold to close. Figure 11 Packaging instructions. Turn the package over to open. Detailed Implementation

[0032] The disclosed pharmaceutical products or approved pharmaceutical products, methods, and uses can be more easily understood by referring to the following detailed description. It should be understood that the disclosed pharmaceutical products or approved pharmaceutical products, methods, and uses are not limited to the specific pharmaceutical products or approved pharmaceutical products, methods, and uses described and / or illustrated herein, and the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to limit the pharmaceutical products or approved pharmaceutical products, methods, and uses protected by the claims.

[0033] Unless otherwise specified, any description of possible mechanisms of action, modes of action, or causes of improvement is intended for illustrative purposes only, and the disclosed pharmaceutical products or approved pharmaceutical products, methods, and uses are not limited by the accuracy of any such suggested mechanisms of action, modes of action, or causes of improvement.

[0034] Throughout this text, descriptions relate to pharmaceutical products or approved pharmaceutical products, methods, and uses. If this disclosure describes or claims a feature or embodiment associated with a pharmaceutical product or approved pharmaceutical product, that feature or embodiment also applies to the described methods and uses. Similarly, if this disclosure describes or claims a feature or embodiment associated with the described methods or uses, that feature or embodiment also applies to the described pharmaceutical product or approved pharmaceutical product.

[0035] Every patent, patent application, and the entire disclosure cited or described in this document is incorporated herein by reference.

[0036] definition As used above and throughout this disclosure, unless otherwise specified, the following terms and abbreviations shall be understood to have the following meanings.

[0037] In this disclosure, unless the context clearly indicates otherwise, the singular forms “a,” “an,” “the,” and “the” include the plural meaning, and references to a given numerical value include at least that value. Thus, for example, a reference to “ingredient” refers to one or more such ingredients, as well as equivalents of that ingredient known to those skilled in the art. Furthermore, when indicating that an element “may be” X, Y, or Z, such usage is in all cases not intended to exclude other options for that element.

[0038] When the term "approximately" is used to indicate an approximation of a value, it should be understood that the specific value constitutes another implementation. For the sake of brevity, some quantitative expressions given herein are not modified by the term "approximately." It should be understood that, whether or not the term "approximately" is explicitly used, each quantity given herein is intended to refer to an actual given value, and also to an approximation of such given values ​​that would be reasonably extrapolated based on ordinary techniques in the art, including approximations of such given values ​​caused by experimental and / or measurement conditions.

[0039] To provide a more concise description, some quantitative expressions in this document are described as a range from approximately X to approximately Y. It should be understood that when describing a range, the range is not limited to the upper and lower limits stated, but should include the entire range from approximately X to approximately Y, or any quantity or range therein. Where applicable, all ranges include end values ​​and are composable. For example, when referring to a range of “1 to 5”, the referenced range should be understood to include ranges such as “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. Furthermore, when a list of alternatives is provided affirmatively, such a list may also include implementations that may exclude any of the alternatives. For example, when describing a range of “1 to 5”, such a description may cover cases where any of 1, 2, 3, 4, or 5 is excluded; therefore, a reference to “1 to 5” may cover “1 and 3 to 5, but excluding 2”, or simply “excluding 2”.

[0040] In the context of pharmaceutical preparations, compositions, or ingredients, the term "acceptable" as used herein means that it does not have a lasting harmful effect on the overall health of the human being receiving the treatment.

[0041] The term "AAP" refers to abiraterone acetate plus prednisolone or prednisolone.

[0042] The term "androgen deprivation therapy (ADT)" refers to a treatment method that reduces the level of androgens produced by the testes of a prostate cancer patient to castration levels (<50 ng / dL) through surgery or medication. This treatment may include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) and / or administration of a luteinizing hormone-releasing hormone ("LHRH") agonist. Examples of LHRH agonists include goserelin acetate, histaminerelin acetate, leuprorelin acetate, and triptorelin palmitate. Physicians may prescribe LHRH agonists based on instructions, advice, and practice. This may include: administering about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably about 3.6 mg to about 10.8 mg of goserelin over a period of about 28 days to about 3 months; administering about 0.01 mg to about 200 mg of leuprorelin acetate over a period of about 3 days to about 12 months, preferably about 3.6 mg of leuprorelin acetate over a period of about 3 days to about 12 months; or administering about 0.01 mg to about 20 mg of triptorelin over a period of about 1 month, preferably about 3.75 mg of triptorelin over a period of 1 month; or administering about 50 mg of histamine relin acetate or about 50 µg of histamine relin acetate daily over a period of 12 months.

[0043] When referring to a pharmaceutical product and at least one medical indication, the term "approved" means a pharmaceutical product containing one or more active pharmaceutical ingredients that has been approved for marketing by a government regulatory agency for the treatment of at least one medical indication. Such government regulatory agencies include, but are not limited to, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), Health Canada, the National Medical Products Administration (NMPA) of China, the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, or similar regulatory agencies in other countries. This disclosure also relates to pharmaceutical products approved by the EMA, FDA, or Health Canada, or similar regulatory agencies in other countries, which contain niraparib and abiraterone acetate, with at least one indication being prostate cancer.

[0044] The term "pharmaceutical product" refers to a pharmaceutical product containing one or more active pharmaceutical ingredients that is marketed for at least one indication, such as prostate cancer.

[0045] The term "ARi" refers to androgen receptor inhibitors.

[0046] The term "BM" refers to biomarkers.

[0047] The term "BPI-SF" refers to the simplified version of the Brief Pain Scale.

[0048] The terms “BRCA+”, “BRCAm”, “BRCA positive status”, or similar terms, refer to mutated or altered forms of the breast cancer genes BRCA1 and BRCA2, whether germline and / or somatic mutations, that are harmful or suspected of being harmful in prostate cancer. BRCA+, BRCAm, or BRCA positive status is determined or detected by approved or validated testing methods.

[0049] As used in this article, the term “cancer” refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner, and in some cases, it refers to metastasis (spread).

[0050] The term "chemotherapy-naïve metastatic castration-resistant prostate cancer" refers to metastatic castration-resistant prostate cancer that has not been previously treated with chemotherapy.

[0051] The term "clinically effective dose" refers to a certain amount of niraparib and abiraterone acetate drug products or approved drug products that can achieve improved overall survival, delayed progression, controlled growth, delayed distant metastasis, improved symptoms or growth of prostate cancer, or improved quality of life of prostate cancer patients (measured by BPI-SF (Brief Version of the Pain Inventory) pain score), as confirmed by efficacy data obtained from clinical trials.

[0052] As used herein, the terms “co-administration” and the like cover the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which these agents are administered via the same or different routes of administration or at the same or different times.

[0053] As used in this article, the term "CRPC" refers to castration-resistant prostate cancer. CRPC is a type of prostate cancer that continues to grow despite the suppression of androgens that provide energy for the growth of prostate cancer cells.

[0054] The transitional terms “comprising,” “substantially consisting of,” and “consisting of” are intended to imply their accepted meaning in patent terminology; that is, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended, and does not exclude additional, unlisted elements or method steps; (ii) “consisting of” excludes any element, step, or component not specified in the claims; and (iii) “substantially consisting of” limits the scope of the claims to the specified material or step “and material or step that does not substantially affect the essential and novel features of the invention protected by the claims.” Embodiments described in the phrase “comprising” (or its equivalents) are also provided, as are those described independently in “consisting of” and “substantially consisting of”.

[0055] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0056] The term "ECOG PS" refers to the performance status of the Eastern Cooperative Oncology Group.

[0057] The terms “HRR+” or “HRRm” refer to genes in the homologous recombination repair gene family that are mutated or altered in form, and these forms are harmful or suspected to be harmful in prostate cancer.

[0058] The terms “excipient” and “carrier” are used interchangeably in this disclosure. The European Pharmacopoeia (Ph.Eur.) defines an excipient as “any component other than the active substance present in or used in the manufacture of a pharmaceutical product. The intended function of the excipient is to act as a carrier (mediator or base) or as a carrier of the active substance, and in doing so contributes to product properties such as stability, biopharmaceutical properties, appearance and patient acceptability, and to facilitate the manufacture of the product. Typically, more than one excipient is used in the formulation of a pharmaceutical product.” The terms mediator and base are further defined in the same pharmacopoeia as: “a mediator is a carrier of the active substance in liquid formulations consisting of one or more excipients” and “a base is a carrier of the active substance in semi-solid and solid formulations consisting of one or more excipients.”

[0059] As used herein, a “fixed-dose combination” (FDC) is a pharmaceutical preparation or composition that contains abiraterone acetate and niraparib, or any pharmaceutically acceptable salt, solvate, or hydrate form thereof (e.g., niraparib tosylate monohydrate), in a single oral dosage form.

[0060] "Free-Dose Combination" (FrDC) refers to a pharmaceutical formulation or composition containing two or more active ingredients, administered to humans in separate dosage forms. Examples include 1) tablets containing abiraterone acetate; and 2) individual tablets containing niraparib and any pharmaceutically acceptable salt, solvate, and hydrate form of niraparib (e.g., niraparib tosylate monohydrate).

[0061] The terms “kit” and “manufactured product” are used as synonyms.

[0062] “Label” or “approved product label” refers to a label for human prescription drugs that (1) contains a summary of the essential scientific information required for the safe and effective use of the drug; and (2) includes prescription information, FDA-approved patient identification (medication guide, patient medication guide, and / or instructions for use), and / or box and container identification. In some implementations, the label or approved product label identifies niraparib and abiraterone acetate, or their trade name Akeega. ® It also provides instructions on its use in patients.

[0063] Prescription information, or "United States Prescription Information (USPI)," reflects the assessment of regulatory agencies (such as the FDA and EMA) regarding the safety and efficacy of prescription drugs for human use under the stated conditions of use. Prescription information is prepared for healthcare professionals and must: 1. A summary containing essential scientific information necessary for the safe and effective use of prescription drugs for human use; 2. The information provided is accurate, and the tone is neither promotional nor false or misleading; and 3. Update the label when new information becomes available that would render it inaccurate, false, or misleading.

[0064] A "medication guide" is a patient identifier and part of the labeling system for FDA-approved prescription drugs. The FDA requires this guide for certain prescription drugs when it determines that: • Patient identification may help prevent serious adverse reactions; • This medication carries serious risks (relative to the benefits) that patients should be aware of, as information about these risks may influence a patient's decision to use or continue using the product; or • Patient adherence to the instructions for use is crucial for the effectiveness of the medication.

[0065] Patient medication guidelines contain information intended for patient use and may be required as part of the labeling of approved drug products.

[0066] Instructions for Use (IFU) are a form of prescription drug labeling typically created for drug products with complex or detailed instructions for patient use, which are reviewed and approved by the FDA under an NDA, BLA, or ANDA, and are usually provided to the patient when the drug product is dispensed.

[0067] According to European law (Article 54 of Council Directive 2001 / 83 / EEC), the following information should appear on the outer packaging of medicines, or, if there is no outer packaging, on the main packaging: (a) The name of the medicine, followed by its strength and form, and (if applicable) whether it is intended for use in infants, children or adults; if the product contains up to three active ingredients, the International Nonproprietary Name (INN) should be included, or if no INN exists, the generic name should be used; (b) Describe the active substance contained in each dose unit or in a specific volume or weight of the administration form in a qualitative and quantitative manner, and use its common name; (c) Dosage form and the weight, volume or dosage of the product; (d) A list of excipients known to have recognized effects or benefits, which is included in the detailed guidance issued pursuant to Section 65. However, if the product is an injectable, or a topical or ocular preparation, all excipients must be listed; (e) Method of administration, and, if necessary, route of administration. Sufficient space should be provided to indicate the prescribed dosage; (f) Special warnings indicating that the medicine must be stored out of the reach and sight of children; (g) Special warning (if necessary for this medicine); (h) Clear expiration date (month / year); (i) Special storage precautions (if any); (j) Specific considerations regarding the disposal of unused pharmaceutical products or pharmaceutical-derived waste (if applicable), and reference to any appropriate existing collection systems; (k) The name and address of the listing permit holder, and (if applicable) the name of the representative designated by the holder to act on its behalf; (l) Drug marketing authorization number; (m) Manufacturer's batch number; (n) For over-the-counter medications, instructions for use; (o) For medicines other than radiopharmaceuticals referred to in section 54a(1), safety features enable wholesale distributors and persons authorized or qualified to supply medicines to the public to: —Verify the authenticity of the medicine, and —Identify individual packages, And a device that allows verification of whether the outer packaging has been tampered with.

[0068] The term “metastatic castration-resistant prostate cancer” or “mCRPC” refers to castration-resistant prostate cancer that has metastasized to other parts of the body, such as the male bones, lymph nodes, or other parts of the body.

[0069] The term "metastatic castration-sensitive prostate cancer" refers to cancer that has spread (metastasized) to other areas of the body, such as bones, lymph nodes, or other parts of the male body, and responds to androgen deprivation therapy (ADT).

[0070] The term "offer of sale" refers to a seller's proposal to a buyer to sell a pharmaceutical product, such as a pharmaceutical composition or oral dosage form.

[0071] The term "overall survival" is defined as the average length of time a patient survives after starting treatment.

[0072] The term "PFS" refers to progression-free survival.

[0073] The term "pharmaceutically acceptable," when used in connection with the compositions described herein, means that the molecular entity and other components of such compositions are physiologically tolerable and generally do not produce adverse effects when administered to humans. The term "pharmaceutically acceptable" also means approved by a federal or state regulatory agency, or listed in the United States Pharmacopeia or other recognized pharmacopoeia for mammals, and more specifically for humans.

[0074] As used herein, the term "drug combination" refers to a product derived from a mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients.

[0075] As used herein, the term "placebo" refers to the administration of a pharmaceutical composition containing abiraterone acetate and prednisone but not niraparib.

[0076] "Progression-free survival after first follow-up treatment" (PFS2) is defined as the time from randomization to the date of progression (radiographic, clinical, or PSA progression) or death from any cause during the first follow-up treatment period (whichever occurs first). General rules for PFS2 events and censoring: 1. For patients who have begun subsequent anti-cancer treatment: a. If disease progression or death occurs during the first subsequent anticancer therapy, this is a PFS2 event, where the date of PFS2 is the minimum of the date of disease progression and the date of death.

[0077] b. If there is no disease progression during the first follow-up cancer therapy and no death before the start of the second follow-up cancer therapy, this is not a PFS2 event, and the subject will be reviewed 1 day after the start date of the second follow-up cancer therapy.

[0078] c. If there is no disease progression and no death during the first follow-up cancer therapy and no second follow-up cancer therapy is started, this is not a PFS2 event, and the subject will be screened at the last known survival date.

[0079] 2. For patients who have not received any subsequent anti-cancer treatment: a. If the patient dies, this is a PFS2 event, with the date of death as the PFS2 date.

[0080] b. If the patient is not dead, this is not a PFS2 event, and the subject will be censored at the last known survival date.

[0081] As used in this article, the term "prostate cancer" refers to prostate adenocarcinoma confirmed by histology or cytology.

[0082] The term "PSA" refers to prostate-specific antigen.

[0083] As used in this article, the term "PSA" 50 "Response" means that serum prostate-specific antigen (PSA) decreases by 50% from baseline.

[0084] The term “radiographic progression-free survival” (rPFS) is defined as the time interval from the randomization date to the date of first radiographic progression or death from any cause (whichever comes first). Radiographic progression is determined by the first occurrence of progression on bone scan (according to PCWG3 criteria) or by the first occurrence of soft tissue lesion progression on CT or MRI (according to RECIST 1.1 criteria).

[0085] Advances in radiology should be evaluated as follows: • Progression of soft tissue lesions as measured by CT or MRI, defined according to RECIST 1.1.

[0086] • Progression of bone lesions as observed by bone scans and PCWG3-based assessment. Under these criteria, any bone progression must be confirmed by a follow-up scan at least 6 weeks later. The week 8 scan (post-first treatment scan) is used as a baseline, and all subsequent scans are compared to it to determine progression. A bone scan is defined as one of the following: 1. Subjects whose week 8 scans show ≥2 new bone lesions will fall into one of the following two categories: a. Subjects whose confirmatory scan (performed after ≥6 weeks) shows ≥2 new lesions compared to the week 8 scan (i.e., a total of ≥4 new lesions compared to the baseline scan) will be considered to have bone scan progression at week 8.

[0087] b. Subjects whose confirmatory scans do not show ≥2 new lesions compared to the week 8 scan will not be considered to have bone scan progression. The week 8 scan will be considered the baseline scan, and subsequent scans will be compared to it. The first scan time point showing ≥2 new lesions compared to the week 8 scan will be considered the bone scan progression time point, provided that these new lesions are confirmed by subsequent scans ≥6 weeks later.

[0088] 2. For patients who did not have ≥2 new bone lesions at week 8 compared to baseline, the first scan showing ≥2 new lesions compared to week 8 will be considered the bone scan progression time point if these new lesions are confirmed in subsequent scans ≥6 weeks later.

[0089] Patients who have not experienced radiographic progression or death will be censored on the date of their last disease assessment if they have never started subsequent anticancer treatment; if they have started subsequent anticancer treatment, they will be censored on the date of their last disease assessment before starting subsequent anticancer treatment. The key censoring rules are summarized below.

[0090] In the context of clinical trial design, the term "randomization" refers to the time it takes for a patient to be identified as eligible for a clinical trial and assigned to a particular treatment group.

[0091] The term “reference preparation (RLD)” refers to an approved pharmaceutical product to which a new generic version must be compared to demonstrate bioequivalence (21 CFR 314.3(b)). It also refers to a pharmaceutical product that has already received marketing authorization from an EU member state or the European Commission based on a complete dossier, i.e., submission of quality, preclinical, and clinical data pursuant to Articles 8(3), 10a, 10b, or 10c of Directive 2001 / 83 / EC, and involves a marketing authorization application for a generic / mixed pharmaceutical product by demonstrating bioequivalence (usually by submitting appropriate bioavailability studies).

[0092] In the United States, companies seeking approval to sell generic equivalents must mention the RLD in their Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on the FDA's finding that the previously approved drug product, the RLD, is safe and effective, and must, among other things, demonstrate that the proposed generic drug product is identical to the RLD in some respects. Specifically, with limited exceptions, the drug product for which an ANDA is submitted must, among other things, have the same active ingredient, conditions of use, route of administration, dosage form, strength, and (with some permissible differences) labeling as the RLD. The RLD is the marketed drug for which the ANDA applicant must demonstrate that its proposed ANDA drug product is identical to the RLD in terms of active ingredient, dosage form, route of administration, strength, labeling, and conditions of use, among other characteristics. The electronic Orange Book will contain sections for RLDs and sections for reference standards. In the printed version of the Orange Book, RLDs and reference standards are identified by specific symbols.

[0093] In Europe, applicants identify the reference medicine (product name, strength, dosage form, marketing authorization holder (MAH), first authorization, member state / community) in their applications for generic / mixed medicines (identical to ANDA or sNDA drug products), which is synonymous with RLD, as described below: 1. A pharmaceutical product authorized or already authorized in the European Economic Area (EEA) serves as the basis for demonstrating that the data protection period as defined in the European Medicines Regulations has expired. This reference pharmaceutical product is determined for the purpose of calculating the expiration of the data protection period and may differ from the generic / hybrid pharmaceutical product in strength, dosage form, route of administration, or presentation.

[0094] 2. Cross-references to pharmaceutical products (product name, strength, form, MAH, marketing authorization number) in generic / hybrid applications. For the purpose of calculating the expiration of data protection periods, the reference pharmaceutical product may have been authorized through a separate process under a different name than the identified reference pharmaceutical product. The product information of this reference pharmaceutical product will, in principle, serve as the basis for the product information protected by the claims for the generic / hybrid pharmaceutical product.

[0095] 3. Medicinal products used in bioequivalence studies (product name, strength, form of medicine, MAH, member country of origin) (where applicable).

[0096] Different simplified approval pathways for drug products under the FD&C Act are described in Sections 505(j) and 505(b)(2) of the FD&C Act (21 USC 355(j) and 21 USC 23 355(b)(2) respectively).

[0097] According to the FDA (www.fda.gov / downloads / Drugs / GuidanceComplianceRegulatoryInformation / Guidances / UCM579751.pdf, the contents of which are incorporated herein by reference), NDAs and ANDAs can be divided into the following four categories: (1) An “independent NDA” is an application filed pursuant to Section 505(b)(1) of the FD&C Act and approved pursuant to Section 505(c) that contains a full report of a safety and effectiveness study performed by or for the applicant or which the applicant has the right to reference or use.

[0098] (2) A 505(b)(2) application is an NDA filed pursuant to section 505(b)(1) of the FD&C Act and approved pursuant to section 505(c), containing a full report of a safety and effectiveness study in which at least some of the information required for approval is derived from a study not performed by the applicant or performed for the applicant and which the applicant has no right to access or use.

[0099] (3) An ANDA is an application submitted and approved under Section 505(j) of the FD&C Act for a copy of a previously approved drug product. An ANDA relies on the FDA's finding that the previously approved drug product (i.e., the Reference Listed Drug (RLD)) is safe and effective. An ANDA must generally include information demonstrating that the proposed generic product (a) is identical to the RLD in terms of active ingredient, conditions of use, route of administration, dosage form, strength, and labelling (with certain permissible differences), and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are required to determine the safety and effectiveness of the proposed product.

[0100] (4) A petition ANDA is an ANDA for a drug product that differs from an RLD in its dosage form, route of administration, strength, or active ingredient (in products having more than one active ingredient), and the FDA, in response to a petition filed under Section 505(j)(2)(C) (Adaptability Request) of the FD&C Act, has ruled that no studies are required to determine the safety and efficacy of the proposed drug product.

[0101] The scientific premise of the Hatch-Waxman Amendment is that a drug product approved in an ANDA under Section 505(j) of the FD&C Act is therapeutically equivalent to its RLD. When administered to a patient under the conditions specified on the label, a product classified as therapeutically equivalent may be substituted, and the substituted product is fully expected to produce the same clinical effects and safety profile as the prescription product. Compared to an ANDA, a 505(b)(2) application allows greater flexibility regarding the characteristics of the proposed product. A 505(b)(2) application will not necessarily be assessed therapeutically equivalent to the marketed drug it referenced at the time of approval.

[0102] The term "safe and effective amount" refers to the amount of active ingredient that, according to the revised Federal Food, Drug, and Cosmetic Act (Sections 201–902, 52 Statute 1040 and later, revised; 21 USC §§ 321–392), elicits a desired biological or pharmaceutical response in a subject's biological system, with the risk not exceeding the benefit of that response. Safety is typically measured through toxicity testing to determine the highest tolerated or optimal dose of the active pharmaceutical ingredient required to achieve the desired beneficial effect. Safety-focused studies also seek to identify any potential adverse effects that may result from exposure to the drug. When tested appropriately, such as in tightly controlled clinical trials, efficacy is typically measured by determining whether the active pharmaceutical ingredient demonstrates a health benefit superior to placebo or other interventions.

[0103] In some implementations, administration of the drug product or approved drug product results in an adverse event of grade 2 or less. In other implementations, administration of the drug product or approved drug product results in an adverse event of grade 3 or less. In still other implementations, administration of the drug product or approved drug product results in an adverse event of grade 4 or less.

[0104] The terms “sale” or “disposal” refer to the transfer of ownership of a pharmaceutical product or approved pharmaceutical product from a seller to a buyer in an arm’s length transaction.

[0105] The terms “subject” and “patient” and “person” are used interchangeably. Typically, a subject, patient, or person is a male subject, patient, or person.

[0106] As used herein, the term "survival benefit" refers to an increase in patient survival from the randomization time of a drug administration trial to death. In some implementations, the survival benefit is approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, approximately 60, approximately 80, approximately 100 months, or greater than 100 months.

[0107] The term "treatment" refers to achieving improved overall survival, delaying progression, controlling growth, postponing distant metastasis, improving symptoms or growth of prostate cancer, or improving the quality of life of patients with prostate cancer (measured by the BPI-SF (Brief Version of the BPI-SF) pain score). Delaying cancer progression includes inhibiting cancer progression, reducing the rate of cancer progression, or stopping the rate of cancer progression.

[0108] The term "time to start cytotoxic chemotherapy" or "time to cytotoxic chemotherapy" (TCC) is defined as the time from randomization to the initiation of a new cytotoxic chemotherapy in a subject (e.g., survival follow-up CRF). The time to initiation of cytotoxic chemotherapy in subjects who have not yet started it is reviewed at the date of their last contact. Surprisingly, treatment of mCRPC is provided by administration of the pharmaceutical product disclosed herein or an approved pharmaceutical product according to the product label, and this effect is measured by the time to cytotoxic chemotherapy.

[0109] The "time to start of subsequent treatment" in the clinical trial design is defined as the period from the randomization date to the date of initiation of subsequent anticancer therapy for prostate cancer. Patients who have not started subsequent anticancer therapy at the time of analysis will have their last visit date preceding their last known survival date, or their last known survival date will be censored. Subsequent anticancer therapy for prostate cancer will include the following categories: chemotherapy, hormone therapy, PARPi, and any other type of prostate cancer therapy.

[0110] The "time to PSA progression" in clinical trial design is defined as the time from randomization to the date PSA progression is first recorded according to PCWG3 criteria. PSA progression is defined as a ≥25% increase in PSA above the lowest point, confirmed by a second value ≥3 weeks later (i.e., confirming an upward trend); and when there is no decrease in baseline: a ≥25% increase in PSA above baseline and ≥2 ng / mL after more than 12 weeks.

[0111] Patients without PSA progression at the time of analysis will be censored on the last known date of no progression. Patients with no baseline PSA or no post-baseline values ​​will be censored on the randomization date.

[0112] The PSA response rate is defined according to PCWG3 criteria as the proportion of subjects who achieved a ≥50% decrease in PSA by week 12 and during treatment, which was confirmed after 3-4 weeks.

[0113] The "time to pain progression" in the clinical trial design was defined as the time from the randomization date to the date on which pain progression was first observed. Pain progression was defined as an increase of 2 points from baseline in the most severe pain intensity (item 3) observed in two consecutive assessments at an interval of ≥3 weeks in the BPI-SF. Subjects who did not experience pain progression at the time of analysis will be reviewed on the last date of the BPI-SF pain score collection.

[0114] The term “time to symptom progression” (TSP) in clinical trial design is defined as the time from randomization to the first occurrence of any of the following events: (i) external beam radiation therapy (EBRT) for skeletal symptoms; (ii) tumor-related orthopedic surgical intervention; (iii) other cancer-related procedures, such as nephrostomy, bladder catheterization, or surgery for non-skeletal tumor symptoms; (iv) initiation of new systemic anticancer therapy for cancer pain; (v) occurrence of cancer-related lesion events, such as fractures, symptomatic and / or pathological spinal cord compression, or urinary tract obstruction. These events are typically documented on a case report form (CRF) and may be reported as (1) occurrence of a skeletal-related event (SRE), such as a pathological fracture, spinal cord compression, or the need for surgical intervention or radiation therapy to the bones; (2) progression or worsening of pain in disease-related symptoms requiring the initiation of new systemic anticancer therapy; or (3) development of clinically significant symptoms due to local tumor progression requiring surgical intervention or radiation therapy. Administration of the pharmaceutical product disclosed herein or an approved pharmaceutical product provides improved treatment for mCRPC, the effect of which is measured by time to symptom progression.

[0115] The implementation scheme disclosed herein This disclosure relates to pharmaceutical products or approved pharmaceutical products having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product comprises niraparib and abiraterone acetate.

[0116] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product comprises niraparib and abiraterone acetate, wherein the at least one indication or approved indication is metastatic castration-resistant prostate cancer (mCRPC).

[0117] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product comprises niraparib and abiraterone acetate, wherein the pharmaceutical product or approved pharmaceutical product is packaged, and wherein the package includes a label that identifies the pharmaceutical product or approved pharmaceutical product as indicated for use with prednisone in the treatment of patients who have been diagnosed with a harmful or suspected harmful breast cancer mutation (BRCAm) mCRPC by a test or approved test.

[0118] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product is indicated in combination with prednisone for the treatment of patients who have a harmful or suspected harmful breast cancer mutation (BRCAm) mCRPC detected by a test or approved test.

[0119] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication for the treatment of prostate cancer with a daily dose of 200 mg niraparib, 1,000 mg abiraterone acetate and 10 mg prednisone, wherein niraparib and abiraterone acetate are administered as a fixed-dose combination pharmaceutical product or as a free-dose combination pharmaceutical product.

[0120] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein the pharmaceutical product or approved pharmaceutical product is administered orally once daily in a dose of 200 mg niraparib and 1,000 mg abiraterone acetate, and in combination with a daily dose of 10 mg prednisone.

[0121] This disclosure relates to a pharmaceutical product or approved pharmaceutical product having at least one indication or approved indication, wherein in cases of myelosuppression accompanied by: (i) a platelet count < 100,000 / mcL, or (ii) a neutrophil count < 1,000 / mcL or a hemoglobin count < 8 g / dL; or in cases of other non-hematologic grade 3 or 4 adverse reactions, the pharmaceutical product or approved pharmaceutical product is administered orally once daily at a reduced dose of 100 mg niraparib and 1,000 mg abiraterone acetate (together with 10 mg prednisone).

[0122] This drug product or approved drug product should be taken on an empty stomach.

[0123] In one implementation plan, no food should be consumed for two hours before and one hour after taking the drug product or approved drug product.

[0124] Patients receiving this drug product or an approved drug product should also receive gonadotropin-releasing hormone (GnRH) analogue therapy concurrently, or the patient should have undergone bilateral orchiectomy.

[0125] GnRH analogues used as ADTs may be selected from, but are not limited to, triptorelin, nafarrelin, goserelin, leuprorelin, or leuprorelin, histidinerelin, gonadorelin, and buserorelin.

[0126] This drug product or approved drug product should not be administered to patients with moderate or severe hepatic impairment.

[0127] This drug product or approved drug product should not be used concurrently with the CYP3A4 inducer rifampin.

[0128] This disclosure relates to a pharmaceutical product or approved pharmaceutical product, wherein the pharmaceutical product or approved pharmaceutical product comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and i. 100 mg niraparib and 500 mg abiraterone acetate, in oral dosage form (normal strength); or ii. 50 mg niraparib and 500 mg abiraterone acetate, in oral formulation (lower strength).

[0129] This disclosure relates to a pharmaceutical product or approved pharmaceutical product that, in patients with harmful or suspected harmful BRCAm mCRPC detected by a test or approved test, induces a median overall survival (OS) of 30.4 months with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

[0130] This disclosure relates to a pharmaceutical product or approved pharmaceutical product in which, after multivariate Cox regression analysis, the median overall survival (OS) hazard ratio (HR) was 0.663 (95% CI: 0.464, 0.947). This multivariate Cox regression analysis adjusted for externally validated and clinically relevant baseline prognostic factors selected from prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (AlkPhos), age, Eastern Cooperative Oncology Group (ECOG) grade, number of bone lesions, and visceral disease.

[0131] This disclosure relates to a pharmaceutical product or approved pharmaceutical product in which, in patients with harmful or suspected harmful BRCAm mCRPC detected by a test or approved test, the pharmaceutical product or approved pharmaceutical product induced an improved median time to symptom progression (TSP) compared with patients receiving placebo and abiraterone acetate plus prednisone, with a HR of 0.562 (95% CI: 0.371, 0.849).

[0132] This disclosure relates to a pharmaceutical product or approved pharmaceutical product in which, in patients with harmful or suspected harmful BRCAm mCRPC detected by a test or approved test, the pharmaceutical product or approved pharmaceutical product elicits an improved median time to cytotoxic chemotherapy (TCC) compared with patients receiving placebo and abiraterone acetate plus prednisone, with an HR of 0.598 (95% CI: 0.387, 0.924).

[0133] This disclosure relates to a pharmaceutical product or approved pharmaceutical product that, in patients with harmful or suspected harmful BRCAm mCRPC detected by a test or approved test, induces a median radiographic progression-free survival (rPFS) of 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0134] This disclosure relates to a pharmaceutical product or an approved pharmaceutical product, wherein the pharmaceutical product or approved pharmaceutical product comprises 159.40 mg of niraparib tosylate monohydrate (equivalent to 100 mg of niraparib free base) as an active ingredient and 500 mg of abiraterone acetate.

[0135] This disclosure relates to a pharmaceutical product or approved pharmaceutical product, wherein the pharmaceutical product or approved pharmaceutical product comprises 79.70 mg of niraparib tosylate monohydrate (equivalent to 50 mg of niraparib free base) as an active ingredient and 500 mg of abiraterone acetate.

[0136] This disclosure relates to a pharmaceutical product or approved pharmaceutical product, wherein the pharmaceutical composition is an oral dosage form selected from film-coated tablets, tablets, capsules, granules and sachets.

[0137] In one embodiment, the pharmaceutical composition is a film-coated tablet, further comprising colloidal anhydrous silica, cropovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate; and a film coating.

[0138] In one embodiment, the film-coated tablet contains 100 mg of niraparib and 500 mg of abiraterone acetate; and the film coating contains iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc, and titanium dioxide.

[0139] In one embodiment, the film-coated tablet contains 50 mg of niraparib and 500 mg of abiraterone acetate; and the film coating contains iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc, and titanium dioxide.

[0140] In one embodiment, the pharmaceutical composition is a capsule containing 100 mg of niraparib and 500 mg of abiraterone acetate, and a pharmaceutically acceptable carrier comprising cropovidone, hydroxypropyl methylcellulose, sodium lauryl sulfate (SLS), lactose monohydrate, and magnesium stearate.

[0141] In one embodiment, the pharmaceutical composition is a capsule containing 50 mg of niraparib and 500 mg of abiraterone acetate, and a pharmaceutically acceptable carrier comprising cropovidone, hydroxypropyl methylcellulose, sodium lauryl sulfate, lactose monohydrate, and magnesium stearate.

[0142] These capsule formulations can contain the active ingredients (niraparib and abiraterone acetate) in granule form. Chloroprene can be replaced by a suitable disintegrant; hydroxypropyl methylcellulose can be replaced by a suitable binder; SLS can be replaced by a suitable wetting agent; lactose monohydrate can be replaced by a suitable diluent or filler; and magnesium stearate can be replaced by a suitable lubricant.

[0143] This disclosure relates to a pharmaceutical product or approved pharmaceutical product that is approved for marketing in the European Economic Area (EEA), Canada, the United States, Japan, China and any other country.

[0144] This disclosure relates to a pharmaceutical product or approved pharmaceutical product, wherein the pharmaceutical product or approved pharmaceutical product is a generic drug, ANDA, sNDA, NDA product, or 505(b)(2) pharmaceutical product.

[0145] This disclosure also relates to a method for treating a patient with mCRPC who has been found to have a harmful or suspected harmful BRCAM by a test or approved test, the method comprising administering the pharmaceutical product or approved pharmaceutical product in combination with prednisone to the patient.

[0146] This disclosure also relates to a method for treating a patient with mCRPC who has been found to have a harmful or suspected harmful BRCAM by a test or approved test, the method comprising administering the pharmaceutical product or approved pharmaceutical product in combination with prednisone to the patient in the amount and manner described in the pharmaceutical product label or approved pharmaceutical product label.

[0147] The method of treating BRCAm mCRPC disclosed herein also includes oral administration once daily of a pharmaceutical product or approved pharmaceutical product containing 200 mg niraparib and 1,000 mg abiraterone acetate, concurrently with daily administration of 10 mg prednisone alone until disease progression or unacceptable toxicity occurs.

[0148] The method of treating BRCAm mCRPC disclosed herein also includes, in cases of myelosuppression accompanied by: (i) a platelet count <100,000 / mcL, or (ii) a neutrophil count <1,000 / mcL or a hemoglobin count <8 g / dL; or in cases of other non-hematologic grade 3 or 4 adverse events, oral administration once daily of a reduced dose of a pharmaceutical product or approved pharmaceutical product containing 100 mg niraparib and 1,000 mg abiraterone acetate, concurrently with daily administration of 10 mg prednisone alone.

[0149] The method disclosed herein for treating BRCAM mCRPC also includes improving median OS to 30.4 months, with a HR of 0.788 (95% CI: 0.554, 1.120).

[0150] In one implementation, median overall survival (OS) was further improved after multivariate Cox regression analysis, with a HR of 0.663 (95% CI: 0.464, 0.947). This multivariate Cox regression analysis adjusted for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

[0151] The method disclosed herein for treating BRCAm mCRPC also includes improvement in median TSP, with an HR of 0.562 (95% CI: 0.371, 0.849).

[0152] The method disclosed herein for treating BRCAm mCRPC also includes improvement in median TCC, with an HR of 0.598 (95% CI: 0.387, 0.924).

[0153] The method disclosed herein for treating BRCAM mCRPC also includes improving median rPFS to 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0154] This disclosure also relates to a method of selling a pharmaceutical product or approved pharmaceutical product comprising niraparib and abiraterone acetate as defined herein, the method comprising selling such pharmaceutical product or approved pharmaceutical product.

[0155] In one implementation scheme, the pharmaceutical product or approved pharmaceutical product is a generic drug, an ANDA pharmaceutical product, a supplemental new drug application pharmaceutical product, an NDA pharmaceutical product, or a 505(b)(2) pharmaceutical product.

[0156] In one implementation, such a pharmaceutical product or a reference formulation of an approved pharmaceutical product improves OS, rPFS, TCC, TSP, or TPP.

[0157] In one implementation, the median overall survival (OS) in the method of marketing the pharmaceutical product or approved pharmaceutical product disclosed herein was 30.4 months, and the hazard ratio (HR) was 0.788 (95% CI: 0.554, 1.120).

[0158] In one embodiment, in the method of marketing or approved pharmaceutical products disclosed herein, the median overall survival (OS) HR was 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis, which adjusted for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

[0159] In one implementation, the median TSP was improved in the method of marketing the pharmaceutical product or approved pharmaceutical product disclosed herein, with a HR of 0.562 (95% CI: 0.371, 0.849).

[0160] In one implementation, the median TCC was improved in the method of marketing the pharmaceutical product or the approved pharmaceutical product disclosed herein, with a HR of 0.598 (95% CI: 0.387, 0.924).

[0161] In one implementation, in the method of marketing a pharmaceutical product or an approved pharmaceutical product disclosed herein, the median rPFS was 19.5 months, with a HR of 0.553 (95% CI: 0.392, 0.782).

[0162] This disclosure also relates to a method of providing or selling a pharmaceutical product or approved pharmaceutical product comprising niraparib and abiraterone acetate as defined herein, the method comprising providing or selling such pharmaceutical product or approved pharmaceutical product.

[0163] In one implementation scheme, the pharmaceutical product or approved pharmaceutical product is a generic drug, an ANDA pharmaceutical product, a supplemental new drug application pharmaceutical product, an NDA pharmaceutical product, or a 505(b)(2) pharmaceutical product.

[0164] In one implementation, such a pharmaceutical product or a reference formulation of an approved pharmaceutical product improves OS, rPFS, TCC, TSP, or TPP.

[0165] In one embodiment of the method of providing or selling a pharmaceutical product or an approved pharmaceutical product disclosed herein, the median overall survival (OS) was 30.4 months, and the hazard ratio (HR) was 0.788 (95% CI: 0.554, 1.120).

[0166] In one implementation, the median overall survival (OS) hazard ratio (HR) was 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis, which adjusted for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

[0167] In one implementation, the median TSP data was improved, with an HR of 0.562 (95% CI: 0.371, 0.849).

[0168] In one implementation, the median TCC data was improved, with an HR of 0.598 (95% CI: 0.387, 0.924).

[0169] In one implementation, the median rPFS was 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0170] This disclosure also relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method for treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone.

[0171] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method for treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises an oral dose of 200 mg niraparib and 1,000 mg abiraterone acetate of said pharmaceutical product or approved pharmaceutical product once daily, and 10 mg prednisone, until disease progression or unacceptable toxicity occurs.

[0172] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method of treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises, once daily, oral administration of a reduced dose of said pharmaceutical product or approved pharmaceutical product containing 100 mg niraparib and 1,000 mg abiraterone acetate, and 10 mg prednisone, in cases of myelosuppression accompanied by: (i) a platelet count < 100,000 / mcL, or (ii) a neutrophil count < 1,000 / mcL or a hemoglobin count < 8 g / dL; or in cases of other non-hematologic grade 3 or 4 adverse events.

[0173] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method of treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises improving median OS to 30.4 months, with a HR of 0.788 (95% CI: 0.554, 1.120).

[0174] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method for treating mCRPC patients with a noxious or suspected noxious BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein, after a multivariate Cox regression analysis, median OS was further improved, with a HR of 0.663 (95% CI: 0.464, 0.947), the multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

[0175] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method for treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises improving median TSP, HR 0.562 (95% CI: 0.371, 0.849).

[0176] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method of treating patients with mCRPC who have been found to have a harmful or suspected harmful BRCAM by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises improving median TCC, HR 0.598 (95% CI: 0.387, 0.924).

[0177] This disclosure relates to a pharmaceutical product or approved pharmaceutical product as defined herein, used in a method of treating mCRPC patients with a harmful or suspected harmful BRCAM detected by a test or approved test, the method comprising administering said pharmaceutical product or approved pharmaceutical product in combination with prednisone, wherein the treatment comprises improving median rPFS to 19.5 months, with a HR of 0.553 (95% CI: 0.392, 0.782).

[0178] This disclosure also relates to a pharmaceutical product or approved pharmaceutical product comprising niraparib and abiraterone acetate, used in combination with prednisone or prednisolone in a method for treating adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1 / 2 mutations (germline and / or somatic mutations) who are not clinically indicated for chemotherapy; wherein BRCA positivity is determined using a validated test method; wherein a single daily dose of the pharmaceutical product or approved pharmaceutical product is 200 mg niraparib and 1,000 mg abiraterone acetate, and a daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity occurs; The treatment is characterized by improving median overall survival (OS) to 30.4 months, with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

[0179] In one implementation, median overall survival (OS) was further improved after multivariate Cox regression analysis, with a HR of 0.663 (95% CI: 0.464, 0.947). This multivariate Cox regression analysis adjusted for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

[0180] In one implementation, the treatment includes improving median TSP, with a HR of 0.562 (95% CI: 0.371, 0.849).

[0181] In one implementation, the treatment includes improving median TCC, with a HR of 0.598 (95% CI: 0.387, 0.924).

[0182] In one implementation, the treatment includes improving median rPFS to 19.5 months, with a HR of 0.553 (95% CI: 0.392, 0.782).

[0183] Nirapani Niraparib is an orally available, highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor with activity against both PARP-1 and PARP-2 DNA repair polymerases. The preparation of niraparib is described in U.S. Patents 8,071,623 and 8,436,185, both of which are incorporated herein by reference.

[0184] As used herein, the term “niraparib” means any of the following: a salt form (including pharmaceutically acceptable salts) of the free base compound (2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide (e.g., 4-methylbenzenesulfonic acid; 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), including hydrated forms (e.g., 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide toluenesulfonate monohydrate). These forms may be referred to as “niraparib free base,” “niraparib toluenesulfonate,” and “niraparib toluenesulfonate monohydrate,” respectively.

[0185] The term “niraparib eq.” or “niraparib equivalent” refers to the free base dose of niraparib.

[0186] In any embodiment of the pharmaceutical product or approved pharmaceutical product, the treatment method using the pharmaceutical product or approved pharmaceutical product, or its medical use as described herein, niraparib is a salt form of tosylate monohydrate. Other niraparib salt forms are also covered in this disclosure, provided that such niraparib salt forms are bioequivalent to niraparib tosylate monohydrate. Examples of such forms are sulfate, benzenesulfonate, fumarate, succinate, camphorate, mandelate, camphorsulfonate, lauryl sulfate, or mixtures of tosylate monohydrate and lauryl sulfate.

[0187] Abiraterone acetate Abiraterone acetate is a compound having the following formula: It is a prodrug of abiraterone, a highly selective, orally active inhibitor of a key enzyme in testosterone synthesis (17α-hydroxylase-C17,20-lyase), also known as a steroid 17α-monooxygenase inhibitor or human cytochrome P450 17α. Inhibition of testosterone synthesis in patients with prostate cancer has been demonstrated with abiraterone acetate. This compound is disclosed in WO 93 / 20097 (A1) and is commercially available, for example, through the brand Zytiga. ® .

[0188] Abiraterone acetate plus prednisone or prednisolone is approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC). Abiraterone acetate tablets are currently marketed as 250 mg or 500 mg oral tablets.

[0189] Prednisone Where “prednisone” is specifically mentioned in this disclosure, those skilled in the art will recognize that prednisone can be replaced by different glucocorticoids, such as prednisolone, hydrocortisone, methylprednisolone, or dexamethasone. Those skilled in the art will know how to substitute prednisone with these other drugs and adjust their dosages (if necessary).

[0190] Particularly suitable glucocorticoids include, but are not limited to: (1) dexamethasone (e.g., decadron, oral; decadron-LA injection, etc.), (2) prednisolone (e.g., Δ-CORTEF). ® Prednisolone acetate (ECONOPRED) ® ), prednisolone sodium phosphate (HYDELTRASOL) ® ), tert-butylprednisolone acetate (HYDELTRA-TBA) ® (etc.), (3) Prednisone (DELTASONE) ® (etc.), or (4) methylprednisolone (e.g., MEDROL) ® (and their combinations). See, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 10th edition, 2001.

[0191] Test or approved test In any implementation of the pharmaceutical product or approved pharmaceutical product, the treatment method using the pharmaceutical product or approved pharmaceutical product, or its medical use as described herein, germline and / or somatic HRR gene alterations, particularly harmful or suspected harmful BRCA mutations (BRCAm genes), are determined by a validated testing method. BRCA genes refer to BRCA1 and BRCA2 genes.

[0192] Examples of commercially available germline and somatic cell tests for prostate cancer are provided below: Tests or approved tests can determine a positive biomarker status for homologous recombination defect (HRD). HRD, also known as homologous recombination repair (HRR) gene defects or alterations, may originate from DNA repair gene defects (DRD) in specific DNA repair genes. HRD or HRR gene alterations encompass DRD as well as gene mutations or alterations outside of DNA repair pathways.

[0193] The HRD (or HRR gene defect or harmful alteration) positive status can be detected by evaluating monoallelic or bialelic, germline and / or somatic alterations in one or more DNA repair genes, or by evaluating genome-wide loss of heterozygosity (LOH) or homozygous harmful alterations in DNA repair genes. HRD (or HRR gene defect or alteration) positive status is also synonymous with PARP biomarker positive status.

[0194] Harmful or suspected harmful DNA repair genes include, but are not limited to: mutated BRCA2 (breast cancer gene 2), mutated BRCA1 (breast cancer gene 1), mutated ATM (ataxia-telangiectasia mutated gene), mutated BRIP1 (BRCA1 interacting protein C-terminal helicase 1 gene), mutated CHEK2 (checkpoint kinase 2 gene), mutated FANCA (Fanconi anemia complement A gene), mutated HDAC2 (histone deacetylase 2), mutated PALB2 (BRCA2 chaperone and localization gene), or mutated CDK12 (cyclin-dependent kinase 12).

[0195] Germline and / or somatic HRR gene alterations are determined using validated assays. HRR status can preferably be evaluated by plasma-based (Resolution Bioscience, Inc.) or tissue-based (Basic Medical Systems, Inc.) assays, particularly by detecting circulating plasma DNA or circulating tumor cells. A list of assays for determining germline and / or somatic HRR gene alterations is provided above and below this document.

[0196] Gene expression profiling and protein biomarkers can also be used for risk stratification of patients with prostate cancer to guide treatment decisions. Commercially available tests include Prolaris. ® (Maryad Genetics, Salt Lake City, Utah); OncotypeDx ® Prostate cancer assay (Genomic Health, Redwood City, CA); ProMark ™ Protein biomarker testing / ProMark ™ Risk scoring (Metamark Genetics, Cambridge, MA); FoundationOne ® CDx (Basic Medical Systems, Cambridge, Massachusetts); FoundationOne ®Liquid CDx (Basic Medical, Cambridge, MA); Caris Molecular Intelligence (Caris Life Sciences, O. Texas); Guardant360 (Quardant Health, Redwood City, California); ProstateNext ® (Ambri Genetics, Aristotle, California); Color Genetic Cancer Test (Color Gene, Burlingame, California); Invitae Prostate Cancer Kit (Invitae, San Francisco, California); Prostate Genetics (Gicon, Cambridge, UK); MyRisk ® Hereditary cancer testing (Maryad Genetics, Salt Lake City, Utah) and Decipher ® A prostate cancer test (GenomeDx Biosciences, San Diego, California) based on the expression patterns of 22 RNA markers in biopsy or radical prostatectomy samples. Prolaris ® OncotypeDx ® and Decipher ® It is a gene expression test based on tissue.

[0197] The test, or approved test, uses samples obtained from prostate cancer patients. These samples can be circulating tumor cells (CTCs), circulating tumor DNA, blood, tissue samples, or tumor biopsy tissue.

[0198] Treatment methods and medical uses Methods of using a pharmaceutical product or approved pharmaceutical product for the treatment of prostate cancer, particularly BRCAm mCRPC as determined by testing or approved testing, comprising, consisting of and / or substantially consisting of the following steps: administering the disclosed pharmaceutical product or approved pharmaceutical product to a patient in need, the amount and manner of administration being described in the product label or approved label of the pharmaceutical product or approved pharmaceutical product.

[0199] It should be understood that the treatment methods described herein include the use of the pharmaceutical product or approved pharmaceutical product in the manufacture of an agent, and the use of the pharmaceutical product or approved pharmaceutical product in the treatment method. Therefore, this document also describes the use of the pharmaceutical product or approved pharmaceutical product in the manufacture of an agent for treating a patient with BRCAmmCRPC as determined by testing or approved testing, wherein the agent is administered in the amount described on the pharmaceutical product label or approved pharmaceutical product label.

[0200] Methods for treating prostate cancer, particularly BRCAm mCRPC, or medical use of the drug product or approved drug product, including, consisting of, and / or substantially consisting of the following steps: administering the drug product or approved drug product to a patient in need, plus a clinically effective amount of a glucocorticoid, such as prednisone or prednisolone.

[0201] The dosing regimens of the oral dosage forms disclosed herein are also disclosed, which include, consist of, and / or consist substantially of the following steps: administration of a dual-drug combination, a combination of, or a fibrillon acetate, of niraparib and abiraterone acetate, plus a clinically effective total amount of glucocorticoids (e.g., prednisone or prednisolone) for the treatment of human prostate cancer.

[0202] Subjects can be castrated surgically or chemically.

[0203] Prior to first taking the drug product or the approved drug product plus prednisone, the patient may have received one or more other types of treatment for prostate cancer. For example, the patient may have received taxane-based chemotherapy before administering the drug product or the approved drug product plus prednisone. Additionally or alternatively, the patient may have received at least one first-line androgen receptor-targeted therapy, such as apatamide and / or enzalutamide, before administering the drug product or the approved drug product plus prednisone. In one respect, the patient was initially unresponsive or became refractory to prior treatment before administering the drug product or the approved drug product plus prednisone.

[0204] The drug product or approved drug product plus prednisone can be taken once daily, at least 1 hour before or at least 2 hours after a meal, in combination of two tablets or two capsules containing niraparib and abiraterone acetate, a dual combination or FDC, and prednisone (in a single dosage form). In one aspect, two tablets or two capsules containing niraparib and abiraterone acetate, a dual combination or FDC, can be taken once daily with water on an empty stomach (at least 1 hour before or at least 2 hours after a meal).

[0205] In one aspect, glucocorticoids are administered once or twice daily. In another aspect, prednisone or prednisolone tablets or capsules are administered once or twice daily.

[0206] In one aspect, one or two tablets or one or two capsules of a combination of niraparib and abiraterone acetate, a dual combination or FDC, are administered once daily, and one or two tablets or one or two capsules of a glucocorticoid (e.g., prednisone) are administered once or twice daily.

[0207] The usual once-daily dose of the pharmaceutical product or approved product is approximately 200 mg niraparib, approximately 500 mg abiraterone acetate, and approximately 10 mg prednisone. A conventional strength oral dosage form of the pharmaceutical product or approved product contains approximately 100 mg niraparib and approximately 500 mg abiraterone acetate. Therefore, the pharmaceutical product or approved product is taken once daily in both oral dosage forms, plus 10 mg prednisone. These two oral dosage forms can be film-coated tablets, tablets, capsules, granule combinations, or sachets. Preferably, the oral dosage form is a film-coated tablet.

[0208] In cases of myelosuppression accompanied by: (i) a platelet count < 100,000 / mcL, or (ii) a neutrophil count < 1,000 / mcL or a hemoglobin count < 8 g / dL; or in cases of other non-hematological grade 3 or 4 adverse reactions requiring dose reduction, the once-daily dose of the drug product or approved drug product is reduced to approximately 100 mg niraparib, approximately 1,000 mg abiraterone acetate, and approximately 10 mg prednisone. A lower-strength oral dosage form of the drug product or approved drug product contains approximately 50 mg niraparib and approximately 500 mg abiraterone acetate. Therefore, the drug product or approved drug product is taken once daily in both oral dosage forms, plus 10 mg prednisone. These two oral dosage forms can be film-coated tablets, tablets, capsules, granule compositions, or sachets. Preferably, the oral dosage form is a film-coated tablet.

[0209] The pharmaceutical products disclosed herein, or approved pharmaceutical products, as well as glucocorticoids administered alone (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone), can be administered to patients with metastatic prostate cancer. Specifically, the dual-drug combination, dual-combination, or FDC pharmaceutical products disclosed herein, or approved pharmaceutical products, as well as glucocorticoids administered alone (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone), can be administered to patients with mCRPC (such as first-line (L1) mCRPC) (e.g., subjects in a metastatic castration-resistant setting who have not received any therapy other than ADT and limited exposure to abiraterone acetate plus prednisone). The patient is HRR-positive, preferably BRCA-positive, as determined by testing or an approved test. Metastatic prostate cancer can be confirmed by a positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI). Patients may have castration levels of testosterone ≤ 50 ng / dL and may be undergoing ADT. Patients may continue ADT. Patients may have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade of 0 or 1.

[0210] If the patient has not undergone surgical castration (i.e., has not undergone bilateral orchiectomy), they may be able to continue ADT treatment while receiving the drug product or the approved drug product plus prednisone (or prednisolone). Patients may have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 1 or less.

[0211] This document also discloses kits comprising pharmaceutical products or approved pharmaceutical products containing niraparib and abiraterone acetate, and optionally, individual compositions containing prednisone or prednisolone, particularly for BRCAm mCRPC as determined by a test or approved test. Instructions for use may be provided for once-daily administration of each composition. For example, the instructions may provide instructions for once-daily administration of a pharmaceutical product or approved pharmaceutical product containing niraparib and abiraterone acetate to a human patient with prostate cancer or BRCAm mCRPC, and instructions for once-daily or twice-daily administration of a composition containing prednisone or prednisolone to the same human patient.

[0212] This disclosure also relates to a method for determining the bioequivalence of a test fixed-dose combination (FDC) formulation of niraparib and abiraterone acetate relative to the pharmaceutical product of this disclosure or an approved pharmaceutical product, the method comprising i) measuring a bioequivalence parameter of the test FDC formulation and optionally measuring a bioequivalence parameter of the pharmaceutical product of this disclosure or an approved pharmaceutical product, and ii) comparing the bioequivalence parameter of the test FDC formulation with the corresponding bioequivalence parameter of the pharmaceutical product of this disclosure or an approved pharmaceutical product.

[0213] In one aspect, the bioequivalence parameter is selected from AUC. (0-t) AUC (0-∞) Remaining area, C max and t max AUC (0-72 h) Terminal rate constant (λ) z ), t 1 / 2 AUC (0-τ) C max,ss t max,ss Ae (0-t) and R max These bioequivalence parameters are well known to those skilled in the fields of bioequivalence and pharmacokinetics.

[0214] Sales methods and methods of providing sales of pharmaceutical products or approved pharmaceutical products This document provides methods for selling pharmaceutical products or approved pharmaceutical products as disclosed herein, the methods including selling such pharmaceutical products or approved pharmaceutical products, wherein the pharmaceutical product label or approved pharmaceutical product label of a reference product of such pharmaceutical product or approved pharmaceutical product includes instructions for treating adult patients with BRCAm mCRPC determined by a test or approved test.

[0215] In some implementations, the sales method includes selling generic drugs, wherein the pharmaceutical product label of the generic drug’s reference product or approved pharmaceutical product includes instructions for treating adult patients with BRCAm mCRPC identified by a test or approved test.

[0216] In another aspect, this document describes a method for marketing the pharmaceutical product or approved pharmaceutical product of this disclosure, the method comprising, consisting of, or substantially consisting of the following steps: placing the pharmaceutical product or approved pharmaceutical product into commercial circulation, wherein the pharmaceutical product or approved pharmaceutical product is accompanied by a package insert containing instructions on the safe and effective use of the pharmaceutical product or approved pharmaceutical product for the treatment of prostate cancer or BRCAm mCRPC.

[0217] This article also provides a method for providing a pharmaceutical product or an approved pharmaceutical product for sale, the method comprising providing a pharmaceutical product or an approved pharmaceutical product for sale, wherein the pharmaceutical product label or approved pharmaceutical product label of the reference product of the pharmaceutical product or the pharmaceutical product includes instructions for treating adult patients with BRCAm mCRPC as determined by a test or approved test.

[0218] In some implementations, the method of offering for sale includes offering for sale a generic drug, wherein the drug product label or approved drug product label of the generic drug includes instructions for treating adult patients with BRCAm mCRPC identified by a test or approved test.

[0219] In some further aspects, this document describes a method of providing a pharmaceutical product or an approved pharmaceutical product for sale, the method comprising, consisting of, or substantially consisting of the following steps: providing the pharmaceutical product or approved pharmaceutical product for commercial distribution, wherein the pharmaceutical product or approved pharmaceutical product is accompanied by a package insert containing instructions on the safe and effective use of the pharmaceutical product or approved pharmaceutical product for the treatment of BRCAm mCRPC.

[0220] In some implementations, the sales method includes selling a kit containing a generic drug, wherein the generic drug's reference product label or approved product label includes instructions for treating patients with BRCAm mCRPC identified by a test or approved test.

[0221] This disclosure also provides a method for providing and selling a kit comprising niraparib and abiraterone acetate, the method comprising providing and selling such a kit wherein the pharmaceutical product label or approved pharmaceutical product label of the reference product for niraparib and abiraterone acetate includes instructions for treating patients with BRCAm mCRPC identified by a test or approved test.

[0222] This article also describes methods for selling kits containing generic or pharmaceutical products or approved pharmaceutical products, wherein the pharmaceutical product label or approved pharmaceutical product label of the generic or pharmaceutical product or approved pharmaceutical product contains overall survival data, adjusted OS data, TSP, TCC or rPFS data.

[0223] Other implementation plans Implementation Scheme 1. An approved pharmaceutical product having at least one indication approved by at least one of the FDA, EMA and Health Canada, wherein the approved pharmaceutical product comprises niraparib and abiraterone acetate.

[0224] Implementation Plan 2. The approved pharmaceutical product according to Implementation Plan 1, wherein at least one approved indication is metastatic castration-resistant prostate cancer (mCRPC).

[0225] Implementation Plan 3. An approved pharmaceutical product according to Implementation Plan 1 or 2, wherein the approved pharmaceutical product is indicated in combination with prednisone for the treatment of patients with a harmful or suspected harmful breast cancer mutation (BRCAm) mCRPC detected by an approved test.

[0226] Implementation Scheme 4. The approved pharmaceutical product according to Implementation Scheme 3, wherein the approved pharmaceutical product is administered orally once daily in a dose of 200 mg niraparib and 1,000 mg abiraterone acetate, and in combination with a daily dose of 10 mg prednisone.

[0227] Implementation Scheme 5. The approved drug product according to Implementation Scheme 3, wherein in cases of myelosuppression accompanied by: (i) platelet count < 100,000 / mcL, or (ii) neutrophil count < 1,000 / mcL or hemoglobin count < 8 g / dL; or in cases of other non-hematological grade 3 or 4 adverse reactions, the approved drug product is administered orally once daily at a reduced dose of 100 mg niraparib and 1,000 mg abiraterone acetate.

[0228] Implementation Scheme 6. An approved pharmaceutical product according to any one of Implementation Schemes 3 to 5, wherein the approved pharmaceutical product is administered on an empty stomach.

[0229] Implementation Plan 7. An approved pharmaceutical product according to any one of Implementation Plans 3 to 6, wherein no food is consumed within two hours before and one hour after taking the approved pharmaceutical product.

[0230] Implementation Plan 8. An approved pharmaceutical product according to any one of Implementation Plans 3 to 7, wherein the patient is simultaneously receiving gonadotropin-releasing hormone (GnRH) analogue treatment or the patient has undergone bilateral orchiectomy.

[0231] Implementation Scheme 9. The approved drug product according to Implementation Scheme 8, wherein the GnRH analogue is selected from triptorelin, nafarelin, goserelin, leuprorelin or leuprorelin, histaminerelin, gonadorelin and buserelin.

[0232] Implementation Plan 10. An approved pharmaceutical product according to any one of Implementation Plans 3 to 9, wherein the approved pharmaceutical product is not administered to patients with moderate or severe hepatic impairment.

[0233] Implementation Scheme 11. An approved pharmaceutical product according to any one of Implementation Schemes 3 to 10, wherein the approved pharmaceutical product is not used in combination with the CYP3A4 inducer rifampin.

[0234] Implementation Scheme 12. An approved pharmaceutical product according to any one of the foregoing implementation schemes, wherein the approved pharmaceutical product comprises a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier; and (i) 100 mg niraparib and 500 mg abiraterone acetate, in oral dosage form (normal strength); or (ii) 50 mg niraparib and 500 mg abiraterone acetate, in oral dosage form (lower strength).

[0235] Implementation Scheme 13. An approved pharmaceutical product according to any one of Implementation Schemes 4 to 12, wherein in patients with harmful or suspected harmful BRCAm mCRPC detected by the approved test, the approved pharmaceutical product induces a median overall survival (OS) of 30.4 months with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

[0236] Implementation Scheme 14. The approved drug product according to Implementation Scheme 13, wherein the median OS HR after multivariate Cox regression analysis is 0.663 (95% CI: 0.464, 0.947), the multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) grade, number of bone lesions, and visceral diseases.

[0237] Implementation Scheme 15. An approved pharmaceutical product according to any one of Implementation Schemes 4 to 14, wherein, in patients with harmful or suspected harmful BRCAm mCRPC detected by approved testing, the approved pharmaceutical product induced an improved median time to symptom progression (TSP) of 0.562 (95% CI: 0.371, 0.849) compared with patients receiving placebo and abiraterone acetate plus prednisone.

[0238] Implementation Scheme 16. An approved pharmaceutical product according to any one of Implementation Schemes 4 to 15, wherein, in patients with harmful or suspected harmful BRCAm mCRPC detected by approved testing, the approved pharmaceutical product elicits an improved median time to cytotoxic chemotherapy (TCC) of 0.598 (95% CI: 0.387, 0.924) compared with patients receiving placebo and abiraterone acetate plus prednisone.

[0239] Implementation Scheme 17. An approved pharmaceutical product according to any one of Implementation Schemes 4 to 16, wherein in patients with harmful or suspected harmful BRCAm mCRPC detected by the approved test, the approved pharmaceutical product induces a median radiographic progression-free survival (rPFS) of 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0240] Implementation Scheme 18. An approved pharmaceutical product according to any one of Implementation Schemes 1 to 17, wherein the approved pharmaceutical product comprises 159.40 mg of niraparib tosylate monohydrate (equivalent to 100 mg of niraparib free base) as an active ingredient and 500 mg of abiraterone acetate.

[0241] Implementation Scheme 19. An approved pharmaceutical product according to any one of Implementation Schemes 1 to 17, wherein the approved pharmaceutical product comprises 79.70 mg of niraparib tosylate monohydrate (equivalent to 50 mg of niraparib free base) as an active ingredient and 500 mg of abiraterone acetate.

[0242] Implementation Scheme 20. An approved pharmaceutical product according to any one of Implementation Schemes 12 to 19, wherein the pharmaceutical composition is an oral dosage form selected from film-coated tablets, tablets, capsules, granules and sachets.

[0243] Implementation Scheme 21. The approved pharmaceutical product according to Implementation Scheme 20, wherein the pharmaceutical composition is a film-coated tablet and further comprises colloidal anhydrous silica, cropovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose and sodium lauryl sulfate; and a film coating.

[0244] Implementation Scheme 22. The approved pharmaceutical product according to Implementation Scheme 21, wherein the film-coated tablet comprises 100 mg niraparib and 500 mg abiraterone acetate; and the film coating comprises iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc and titanium dioxide.

[0245] Implementation Scheme 23. The approved pharmaceutical product according to Implementation Scheme 21, wherein the film-coated tablet comprises 50 mg niraparib and 500 mg abiraterone acetate; and the film coating comprises iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc, and titanium dioxide.

[0246] Implementation Scheme 24. An approved pharmaceutical product according to any one of the preceding implementation schemes, wherein the approved pharmaceutical product is approved for marketing in the European Economic Area (EEA) or Canada.

[0247] Implementation Scheme 25. An approved pharmaceutical product according to any one of the preceding implementation schemes, wherein the approved pharmaceutical product is a generic drug, ANDA, sNDA, NDA product, or 505(b)(2) pharmaceutical product.

[0248] Implementation Scheme 26. A method for treating a patient with mCRPC who has been found to have a harmful or suspected harmful BRCAM by an approved test, the method comprising administering to the patient a combination of an approved pharmaceutical product as defined in any of the preceding embodiments and prednisone.

[0249] Implementation Scheme 27. The method for treating mCRPC according to Implementation Scheme 26, wherein the treatment method comprises oral administration once daily of an approved pharmaceutical product containing 200 mg niraparib and 1,000 mg abiraterone acetate, concurrently with daily administration of 10 mg prednisone alone until disease progression or unacceptable toxicity occurs.

[0250] Implementation Scheme 28. The method for treating mCRPC according to Implementation Scheme 26, wherein the treatment comprises, once daily, oral administration of the approved drug product containing 100 mg niraparib and 1,000 mg abiraterone acetate in cases of myelosuppression accompanied by: (i) platelet count < 100,000 / mcL, or (ii) neutrophil count < 1,000 / mcL or hemoglobin count < 8 g / dL; or in cases of other non-hematologic grade 3 or 4 adverse reactions, concurrently with daily administration of 10 mg prednisone alone.

[0251] Implementation Scheme 29. A method for treating mCRPC according to any one of Implementation Schemes 26 to 28, wherein the treatment method comprises improving the median OS to 30.4 months, with a HR of 0.788 (95% CI: 0.554, 1.120).

[0252] Implementation Scheme 30. The method for treating mCRPC according to Implementation Scheme 29, wherein the median OS was further improved after multivariate Cox regression analysis, with a HR of 0.663 (95% CI: 0.464, 0.947), the multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, AlkPhos, age, ECOG grade, number of bone lesions, and visceral disease.

[0253] Implementation Scheme 31. A method for treating mCRPC according to any one of Implementation Schemes 26 to 30, wherein the treatment comprises improving median TSP, with a HR of 0.562 (95% CI: 0.371, 0.849).

[0254] Implementation Scheme 32. A method for treating mCRPC according to any one of Implementation Schemes 26 to 31, wherein the treatment comprises improving median TCC, with a HR of 0.598 (95% CI: 0.387, 0.924).

[0255] Implementation Scheme 33. A method for treating mCRPC according to any one of Implementation Schemes 26 to 32, wherein the treatment comprises improving median rPFS to 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0256] Implementation Scheme 34. A method of selling an approved pharmaceutical product comprising niraparib and abiraterone acetate as defined in any one of Implementation Schemes 1 to 25, said method comprising selling such approved pharmaceutical product.

[0257] Implementation Scheme 35. The sales method according to Implementation Scheme 34, wherein the approved drug product is a generic drug, an ANDA drug product, a supplemental new drug application drug product, an NDA product, or a 505(b)(2) drug product.

[0258] Implementation Scheme 36. The sales method according to Implementation Scheme 34 or 35, wherein the reference formulation of such approved drug product improves OS, rPFS, TCC, TSP or TPP.

[0259] Implementation Scheme 37. The sales method according to Implementation Scheme 36, wherein the median OS is 30.4 months and the HR is 0.788 (95% CI: 0.554, 1.120).

[0260] Implementation Scheme 38. The sales method according to Implementation Scheme 37, wherein the median OS HR after multivariate Cox regression analysis is 0.663 (95% CI: 0.464, 0.947), the multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions and visceral diseases.

[0261] Implementation Scheme 39. The sales method according to any one of Implementation Schemes 36 to 38, wherein the median TSP is improved to 0.562 (95% CI: 0.371, 0.849).

[0262] Implementation Scheme 40. The sales method according to any one of Implementation Schemes 36 to 39, wherein the median TCC is improved to 0.598 (95% CI: 0.387, 0.924).

[0263] Implementation Scheme 41. The sales method according to any one of Implementation Schemes 36 to 40, wherein the median rPFS is 19.5 months and the HR is 0.553 (95% CI: 0.392, 0.782).

[0264] Implementation Scheme 42. A method of providing and selling an approved pharmaceutical product comprising niraparib and abiraterone acetate as defined in any one of Implementation Schemes 1 to 25, said method comprising providing and selling such approved pharmaceutical products.

[0265] Implementation Scheme 43. Providing a sales method according to Implementation Scheme 42, wherein the approved drug product is a generic drug, an ANDA drug product, a supplemental new drug application drug product, an NDA product, or a 505(b)(2) drug product.

[0266] Implementation Scheme 44. Providing a marketing method according to Implementation Scheme 42 or 43, wherein the reference formulation of such approved drug product improves OS, rPFS, TCC, TSP, or TPP.

[0267] Implementation Scheme 45. Providing a sales method according to Implementation Scheme 44, wherein the median OS is 30.4 months and the HR is 0.788 (95% CI: 0.554, 1.120).

[0268] Implementation Scheme 46. Providing the sales method according to Implementation Scheme 45, wherein the median OS HR is 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis, the multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions and visceral diseases.

[0269] Implementation Scheme 47. Providing a sales method according to any one of Implementation Schemes 44 to 46, wherein the median TSP is improved to 0.562 (95% CI: 0.371, 0.849).

[0270] Implementation Scheme 48. Providing a sales method according to any one of Implementation Schemes 44 to 47, wherein the median TCC is improved to 0.598 (95% CI: 0.387, 0.924).

[0271] Implementation Scheme 49. Providing a sales method according to any one of Implementation Schemes 44 to 48, wherein the median rPFS is 19.5 months and the HR is 0.553 (95% CI: 0.392, 0.782).

[0272] Implementation Scheme 50. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in a method for treating mCRPC patients with a harmful or suspected harmful BRCAM detected by an approved test, the method comprising administering the approved pharmaceutical product in combination with prednisone.

[0273] Implementation Scheme 51. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of Implementation Scheme 50, wherein the treatment comprises oral administration once daily of the approved pharmaceutical product in a dose containing 200 mg niraparib and 1,000 mg abiraterone acetate, and 10 mg prednisone until disease progression or unacceptable toxicity occurs.

[0274] Implementation Scheme 52. The approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of Implementation Scheme 50, wherein the treatment includes, once daily, oral administration of the approved pharmaceutical product containing a reduced dose of 100 mg niraparib and 1,000 mg abiraterone acetate, and 10 mg prednisone, in cases of myelosuppression accompanied by: (i) a platelet count < 100,000 / mcL, or (ii) a neutrophil count < 1,000 / mcL or a hemoglobin count < 8 g / dL; or in cases of other non-hematologic grade 3 or 4 adverse reactions.

[0275] Implementation Scheme 53. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of any one of Implementation Schemes 50 to 52, wherein the treatment method includes improving the median OS to 30.4 months, with a HR of 0.788 (95% CI: 0.554, 1.120).

[0276] Implementation Scheme 54. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of Implementation Scheme 53, wherein the median OS is further improved after multivariate Cox regression analysis, with a HR of 0.663 (95% CI: 0.464, 0.947), wherein the multivariate Cox regression analysis adjusts for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral diseases.

[0277] Implementation Scheme 55. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of any one of Implementation Schemes 50 to 54, wherein the treatment includes improving the median TSP, with an HR of 0.562 (95% CI: 0.371, 0.849).

[0278] Implementation Scheme 56. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of any one of Implementation Schemes 50 to 55, wherein the treatment includes improving the median TCC, with a HR of 0.598 (95% CI: 0.387, 0.924).

[0279] Implementation Scheme 57. An approved pharmaceutical product as defined in any one of Implementation Schemes 1 to 25 above, used in the method of any one of Implementation Schemes 50 to 56, wherein the treatment includes improving median rPFS to 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0280] Implementation Scheme 58. An approved pharmaceutical product comprising niraparib and abiraterone acetate, used in combination with prednisone or prednisolone in a method for treating adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1 / 2 mutations (germline and / or somatic mutations) for whom chemotherapy is not clinically indicated; wherein BRCA positive status is determined using a validated test method; wherein a single daily dose of the approved pharmaceutical product is 200 mg niraparib and 1,000 mg abiraterone acetate, and a daily dose of prednisone or prednisolone is 10 mg, until disease progression or unacceptable toxicity occurs; The treatment is characterized in that it improves the median overall survival (OS) to 30.4 months, with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

[0281] 59. The approved pharmaceutical product used according to Implementation Scheme 58, wherein the median overall survival (OS) was further improved after multivariate Cox regression analysis, with a hazard ratio (HR) of 0.663 (95% CI: 0.464, 0.947). The multivariate Cox regression analysis adjusted for external validation and clinically relevant baseline prognostic factors selected from PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral diseases.

[0282] 60. An approved pharmaceutical product used according to embodiment 58 or 59, wherein the treatment comprises improving the median TSP, with a HR of 0.562 (95% CI: 0.371, 0.849).

[0283] 61. An approved pharmaceutical product used according to any one of embodiments 58 to 60, wherein the treatment comprises improving the median TCC, with a HR of 0.598 (95% CI: 0.387, 0.924).

[0284] 62. An approved pharmaceutical product used according to any one of embodiments 58 to 61, wherein the treatment includes improving the median rPFS to 19.5 months, with an HR of 0.553 (95% CI: 0.392, 0.782).

[0285] This disclosure is further defined in the following embodiments, which include unexpected and advantageous results. It should be understood that while these embodiments indicate preferred embodiments of this disclosure, they are given by way of example only and should not be construed as limiting the appended claims. Based on the foregoing discussion and these embodiments, those skilled in the art can determine the essential features of this disclosure and can make various changes and modifications to suit various uses and conditions without departing from the spirit and scope of this disclosure.

[0286] Example Example 1 – Final analysis of the MAGNITUDE study: including cohort 1 BRCA subgroup (225 participants) Results: Efficacy outcomes of 113 subjects in the niraparib + AAP group and 112 subjects in the placebo + AAP group, and team Cohort 1 presents safety results for the entire HRR population. This example also summarizes updated results from Cohort 3. .

[0287] Research Design The MAGNITUDE study was a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of once-daily niraparib 200 mg in combination with abiraterone acetate (AA) 1,000 mg plus prednisone 10 mg, versus placebo in combination with abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Subjects were prospectively recruited into either cohort 1 or cohort 2 based on the presence or absence of homologous recombination repair (HRR) gene alterations. Additionally, after enrollment in cohorts 1 and 2, a separate open-label cohort, cohort 3, was enrolled to obtain clinical experience with the fixed-dose combination (FDC) tablet formulation of niraparib and AA in combination with prednisone.

[0288] Study population Male participants aged 18 years or older with mCRPC and with or without HRR gene alterations, who have not been treated in a metastatic castration-resistant background (except for limited exposure to AAP and continuous ADT), are eligible to participate in this study.

[0289] • Cohort 1: Subjects with HRR gene alterations – involving alterations in the BRCA1, BRCA2, ATM, BRIP1, CDK12, CHEK2, HDAC2, FANCA, or PALB2 genes.

[0290] • Cohort 2: Subjects without HRR gene alterations – This cohort meets the invalidity criteria described below.

[0291] • Cohort 3: Subjects with HRR gene alterations – same as those listed in Cohort 1.

[0292] All participants were enrolled after undergoing HRR gene alteration testing using Foundation One CDx tissue assay, Resolution HRD plasma assay, Amoy Dx blood and tissue assay (China only), or a recognized local laboratory biomarker test that has been reviewed and certified by the center to indicate pathogenic germline or somatic alterations.

[0293] Randomization Participants were randomly assigned in a 1:1 ratio to receive either niraparib + AAP or placebo + AAP, and stratified according to the following factors: prior exposure to taxane-based chemotherapy (yes or no); prior exposure to AR-targeted therapy (enzalutamide or apalutamide, compared to no exposure) in the context of mHSPC or nmCRPC; and prior use of AAP in mCRPC (yes or no). Cohort 1 was also stratified by gene mutation group (BRCA1 or BRCA2 compared to all other HRR gene alterations).

[0294] Treatment duration / Trial duration The study consists of the following phases: a pre-screening phase for biomarker evaluation only, a screening phase, a treatment phase, and a follow-up phase for collecting secondary endpoints. Treatment continues until clear clinical progression, unacceptable toxicity, death, or termination of the study by the sponsor. Treatment may be discontinued upon confirmation of radiographic progression based on central imaging review.

[0295] Main objectives : • Evaluate the efficacy of niraparib and AAP compared to AAP and placebo. Secondary objectives : • Evaluate the clinical benefit of niraparib and AAP compared to AAP and placebo. • Characterize the safety profile of niraparib when administered with AAP compared to AAP and placebo. Key therapeutic variables Radiographic progression-free survival (rPFS) assessed by blinded central review (BICR) is defined as the time interval from the randomization date to the date on which the BICR determines the first radiographic progression or death from any cause (whichever comes first).

[0296] Primary and secondary therapeutic variables • Time to symptom progression (TSP) is defined as the time from randomization to the first occurrence of any of the following events: External beam radiotherapy (EBRT) ○ Tumor-related orthopedic surgical intervention ○ Cancer-related procedures (e.g., nephrostomy tube insertion, or surgery for non-bone tumor symptoms) ○Starting a new systemic anti-cancer treatment due to cancer pain ○ Cancer-related events (e.g., fractures, spinal cord compression, urinary tract obstruction) • Time to cytotoxic chemotherapy (TCC) • Total OS The main analysis set of therapeutic effects The efficacy analysis of cohort 1 used data from randomized subjects in cohort 1.

[0297] Research drug information All study treatments were provided directly by the sponsor. For Cohort 1 and Cohort 2, niraparib was provided in 100 mg capsules for oral administration. The placebo of niraparib was provided in capsule formulation and matched in size, color, and shape to maintain blinding of the study. AA was provided in 250 mg tablets for oral administration, and prednisone was provided in 5 mg tablets for oral administration.

[0298] For cohort 3, niraparib / AA FDC is provided as a regular strength tablet containing 100 mg niraparib / 500 mg AA per tablet. Prednisone is provided as a 5 mg tablet for oral administration. If dose adjustment of niraparib is required, a low strength (LS) FDC tablet containing 50 mg / 500 mg niraparib / AA per tablet is also available. For subjects who need to discontinue one drug due to toxicity, a single dose of niraparib is available as a 100 mg capsule and AA is available as a 250 mg tablet, both for oral administration.

[0299] Dosage and administration Subjects in cohort 1 and cohort 2 were randomized in a 1:1 ratio to receive 200 mg niraparib, 1,000 mg AA, and 10 mg prednisone daily (niraparib + AAP) and / or a matched placebo, 1,000 mg AA, and 10 mg prednisone daily (PBO + AAP). Subjects in cohort 3 received 200 mg niraparib / 1,000 mg AAP (hereinafter referred to as FDC) and 10 mg prednisone daily (FDC + P).

[0300] The study treatment should be taken on an empty stomach in the morning, with no food for at least 2 hours before and at least 1 hour after administration. The study treatment should be swallowed whole with water. Except for prednisone, which is taken twice daily, all other study treatments should be taken concurrently. If a subject forgets to take the study treatment at the scheduled time, the missed dose should only be taken if the subject remembers on the same day.

[0301] Patients who have not undergone castration surgery must receive background GnRHa therapy to maintain castration-level testosterone concentrations (≤50 ng / dL). The choice of GnRHa is determined by the investigator. The dosage and dosing regimen (uninterrupted) should be consistent with the prescribing information for the GnRHa agent used and should only be adjusted if clinically indicated to maintain castration-level testosterone concentrations.

[0302] Contraindicated concomitant drugs The following medications / therapies are prohibited during the study: • Investigational drugs other than research treatments • Other anti-cancer therapies • Other agents that target the androgen axis (e.g., anti-androgens such as enzalutamide and apalutamide, or CYP17 inhibitors such as ketoconazole). • Testosterone • Radiation therapy targeting tumor progression. Subjects may receive palliative radiation therapy in specific circumstances, subject to discussion with the initiator.

[0303] Chemotherapy • Immunotherapy • Diethylhexestrol or similar estrogen receptor agonists • Pomegranate and pomegranate juice • Spironolactone • Radiopharmaceuticals, such as radium-223, strontium, or samarium. • Strong inducers of CYP3A4 (e.g., rifampin) Restricted concomitant drugs The potential drug interaction between niraparib and AAP limits the use of the following drugs: • CYP2D6 substrates: Caution is advised when AA is administered co-administered with pharmaceuticals activated or metabolized by CYP2D6, especially those with a narrow therapeutic index. Consideration should be given to reducing the dosage of pharmaceuticals metabolized by CYP2D6 with a narrow therapeutic index.

[0304] • CYP2C8 substrates: In a CYP2C8 drug-drug interaction study in healthy subjects, the AUC of pioglitazone increased by 46% when administered co-administered with a single dose of 1,000 mg AA. Although no clinically meaningful increase in exposure was observed when AA was combined with drugs primarily eliminated by CYP2C8, subjects should be monitored for signs of toxicity associated with CYP2C8 substrates with narrow therapeutic indices if used concomitantly with AA.

[0305] Selection criteria Subjects need to meet the following main inclusion criteria: 1. Possessing the following HRR gene alteration status (as identified by assays requested by the initiator or by local testing for HRR gene alteration): a. Cohort 1: Positive for HRR gene alterations b. Cohort 2: Not positive for HRR gene alterations (i.e., no HRR gene alterations). c. Cohort 3: Positive for HRR gene alterations 2. Metastatic disease with a record of metastatic lesions on a positive bone scan, CT, or MRI.

[0306] 3. Metastatic prostate cancer in an environment where castration levels of testosterone are ≤ 50 ng / dL during GnRHa or bilateral orchiectomy, as confirmed by PSA progression or radiographic progression.

[0307] 4. If surgical castration is not performed, GnRHa can be continued during the study period.

[0308] 5. Has an ECOG fitness rating of 0 or 1.

[0309] 6. A score ≤3 on item 3 of the BPI-SF questionnaire (most severe pain in the last 24 hours).

[0310] 7. Clinical laboratory values ​​at screening: a.ANC ​​≥1.5 ×10 9 / L.

[0311] b. Hemoglobin ≥ 9.0 g / dL (unrelated to blood transfusion) for at least 30 days.

[0312] c. Platelet count ≥100×10 9 / L.

[0313] Exclusion criteria If a subject meets any of the following key exclusion criteria during the pre-study screening, the subject must not be recruited into the study: 1. Previous treatment with PARP inhibitors.

[0314] 2. Those who have received systemic therapy in the context of mCRPC (i.e., novel second-generation AR-targeted therapy, such as enzalutamide, apatamide, or dalotamide; taxane-based chemotherapy; or AAP more than 4 months prior to randomization); or AAP outside the mCRPC setting.

[0315] 3. Subjects who have received AAP for 2 to 4 months prior to randomization should show no signs of PSA progression during screening (according to PCWG3). These potential subjects need to have two PSA values ​​during the pre-screening and screening phases. The second PSA value should occur within 2 weeks of randomization, and the PSA elevation should be believed to be due to a disease onset, with investigators confirming no radiographic progression.

[0316] 4. Presence of uncontrolled hypertension (persistent systolic blood pressure (BP) ≥160 mmHg or diastolic blood pressure ≥100 mmHg). Subjects with a history of hypertension are permitted to participate if BP is controlled within these limits through antihypertensive treatment.

[0317] 5. Subjects who received any of the following treatments within ≤ 28 days prior to randomization: a. Blood transfusion (platelets or red blood cells).

[0318] b. Hematopoietic growth factor.

[0319] c. Research drugs for prostate cancer.

[0320] d. Major surgery (Consult the initiator about what constitutes major surgery).

[0321] e. Radiation therapy Expected effect size and planned sample size Cohort 1: Approximately 400 participants with mCRPC and HRR gene alterations were randomized 1:1 to receive either niraparib + AAP or PBO + AAP to observe approximately 220 rPFS events and provide 87% detectability at a two-sided significance level of 0.05 (assumed HR 0.65). Approximately 50% of participants had BRCA1 or BRCA2 (BRCA) alterations to generate approximately 102 rPFS events in the BRCA subgroup and provide 93% detectability at a two-sided significance level of 0.05 (assumed HR 0.50).

[0322] Cohort 2: If the waste factor test was not met, approximately 600 participants with mCRPC without HRR gene alterations were randomized 1:1 to receive either niraparib + AAP or PBO + AAP. A pre-planned waste factor analysis was performed on this cohort, recruiting 247 participants (excluding 14 participants with CDK12 alterations). Recruitment for Cohort 2 was stopped when the waste factor test was met. Participants were unblinded (except for the 14 participants with CDK12 alterations), and the principal investigator determined, based on the benefit and risk assessment, whether to continue with niraparib + AAP, niraparib (if AAP is discontinued due to toxicity), or discontinue niraparib + AAP and receive AAP alone.

[0323] Cohort 3: Approximately 100 subjects with HRR gene alterations (about half of whom had BRCA alterations) were recruited into Cohort 3.

[0324] Uselessness analysis for queue 2 A pre-planned uselessness analysis was conducted on August 13, 2020, for cohort 2, which enrolled 247 participants. When 113 composite progression events (preceding PSA progression, radiographic progression, or death) were observed (40 rPFS events and 73 PSA events), the pre-planned uselessness criterion of HR > 1 was met, with a HR of 1.087 and 95% CI of (0.751, 1.571) for the composite progression endpoint, and uselessness was declared for this cohort. During the uselessness analysis, the time to PSA progression was also analyzed (83 PSA events, HR = 1.032, 95% CI of (0.671, 1.588)), and rPFS analysis was also performed (65 rPFS events, HR = 1.027, 95% CI of (0.631, 1.671)). The Independent Data Monitoring Committee (IDMC) recommended that “treatment / enrollment for subjects in this cohort may be terminated.” The sponsoring committee accepted the IDMC’s recommendation, stopped recruitment, and unblinded the cohort. Subjects with CDK12 mutations in cohort 2 were excluded from the waste-of-use analysis and remained blinded. As part of Amendment 3, these subjects were included in the sensitivity analysis along with those prospectively randomized to cohort 1. Unblinded subjects were given the option to continue niraparib or continue AAP alone. Subjects continued to be followed up on safety.

[0325] Statistical testing strategy for the primary endpoint The primary endpoint of the study, rPFS, was defined as the time interval from the date of randomization to the first date of radiographic progression or death from any cause (whichever occurred first), as assessed by blinded independent central review (BICR). Chest, abdominal, and pelvic CT or MRI scans and whole-body skeletal scans were used. 99m Tc) Evaluation of BICR. Given that cohort 2 satisfies the uselessness condition, the overall statistical approach was to test the primary endpoint of rPFS in cohort 1, with a total α of 0.05. Within cohort 1, rPFS was first tested in the BRCA subgroups of cohort 1 at α = 0.05 (two-tailed). If the result was statistically significant, rPFS was tested across the entire cohort 1 at α = 0.05 (two-tailed) based on a predefined test gradation. An analysis of rPFS in the non-BRCA subgroups of cohort 1 was pre-planned in SAP, but no formal statistical testing procedures were performed for this analysis, nor were α values ​​assigned.

[0326] Interim analysis of secondary endpoints In Cohort 1, two interim analyses (IAs) and one final analysis were planned for the primary secondary endpoints using a group-order design approach: overall survival (OS) and time to symptomatic progression (TSP), defined as the time required to initiate: EBRT for skeletal symptoms, tumor-related orthopedic surgical intervention, other cancer-related procedures (e.g., nephrostomy, bladder catheterization, EBRT, or surgery for tumor symptoms other than skeletal), new systemic anticancer therapy due to cancer pain or cancer-related pathological events (e.g., symptomatic and / or pathological fractures, spinal cord compression, urinary tract obstruction), and time to cytotoxic chemotherapy (TCC). If the rPFS result in Cohort 1 was statistically significant, all three secondary endpoints were tested simultaneously, allowing for alpha recirculation using the group-order design approach.

[0327] Analytical methods The time-event endpoints were estimated using Kaplan-Meier estimates of the survival distribution, and HRs and associated 95% confidence intervals were obtained using a stratified Cox model. These other power endpoints were tested using a stratified log-rank test.

[0328] ORR and PSA response rates were summarized by treatment group using descriptive statistics (counts and percentages). Relative risks were reported along with the corresponding two-sided 95% CI. The two treatment groups were compared using the chi-square test; Fisher's exact test was used if the expected count in some cells was less than 5.

[0329] Research Results Summary of Interim Analysis 1 (IA1) and 2 (IA2) At the primary analysis of rPFS (IA1 for the secondary endpoint; Clinical Cutoff (CCO) date: October 8, 2021; median follow-up time for cohort 1 and BRCA subgroup: 18.6 months and 16.7 months, respectively), niraparib + AAP showed statistically significant and clinically meaningful improvements in rPFS in both the predefined BRCA subgroup and all HRR populations (cohort 1). At IA2 (CCO: June 17, 2022; median follow-up time for cohort 1 and BRCA subgroup: 26.8 months and 24.8 months, respectively), statistically significant and clinically meaningful prolongations of TSP were observed in all HRR populations and also in the BRCA subgroup. Treatment with niraparib + AAP also resulted in prolonged TCC in all HRR populations and the BRCA subgroup (Table 1).

[0330] Table 1: rPFS, TSP, and TCC results at PA-IA1 and IA2 for all HRR populations and BRCA subgroups * The HR estimates are derived from a stratified Cox proportional hazards model.

[0331] ** The p-value is based on the stratified log-rank test.

[0332] # It has statistical significance ## Nominal p-value As shown in Table 1 above, at IA2, the observed HR for OS in the BRCA subgroup was 0.881. Multivariate analysis considering baseline characteristic imbalances in subjects showed that treatment with niraparib plus AAP was associated with favorable survival, HR=0.682; 95% CI: 0.445, 1.046. Data for all HRR populations remained confounded by baseline characteristic imbalances, and multivariate analysis (HR=0.815; 95% CI: 0.603, 1.101) strongly indicated that treatment with niraparib plus AAP did not impair OS.

[0333] OS Final Analysis (FA) Summary (CCO Date: May 15, 2023) The final analysis, as pre-configured by SAP, was performed when approximately 246 OS events (deaths) were observed in Cohort 1. Given that the BICR scan was discontinued after IA2, the rPFS analysis was not updated at FA, but all secondary endpoints for all HRR populations and BRCA subgroups were evaluated using more mature data. This report also provides the PRO analysis for the BRCA subgroups, along with updated safety data.

[0334] All p-values ​​according to SAP are two-sided, and the p-values ​​for secondary endpoint analysis during FA in the BRCA population are nominal p-values.

[0335] Cohort 1, Final Efficacy Analysis (BRCA Subgroup) At the FA CCO (May 15, 2023), the median follow-up duration for BRCA participants in Cohort 1 was 35.9 months (an increase of 11.1 months since IA2). A total of 240 deaths were observed across the entire HRR population in Cohort 1 (98% of the planned SAP FA events), with 130 deaths in the BRCA subgroup. The median duration of treatment for BRCA participants in the niraparib + AAP group was 20.5 months, compared to 14.4 months in the placebo + AAP group.

[0336] Since no formal statistical tests are planned for the secondary endpoints of the BRCA subgroups, nominal p-values ​​are provided for descriptive purposes.

[0337] Overall survival (OS) of the BRCA subgroup In the BRCA subgroup, more deaths were observed in the placebo + AAP group (70 / 112, 62.5%), compared to (60 / 113, 53.1%) in the niraparib + AAP group. OS at FA showed a strong trend toward improved OS with niraparib + AAP treatment in subjects with BRCA alterations (p=0.1828) (HR=0.788; 95% CI: 0.554, 1.120), and the Kaplan-Meier curves showed significant separation between the treatment groups with prolonged follow-up. Figure 1 The median overall survival (OS) was 30.4 months in the niraparib + AAP group and 28.6 months in the placebo + AAP group.

[0338] Multivariate analysis of OS in BRCA subgroups Imbalance in baseline characteristics between treatment groups: As described in the IA2 Clinical Research Report (CSR), several key baseline factors known as survival predictors (Armstrong 2020; Halabi 2014; Lin 2009) were imbalanced between treatment groups, potentially adversely affecting the niraparib + AAP group. These imbalances include: • The proportion of participants with a baseline ECOG PS score of 1 in the niraparib + AAP group (38.7%) was higher than that in the placebo + AAP group (30.8%). • The proportion of participants aged ≥75 years in the niraparib + AAP group (29.7%) was higher than that in the placebo + AAP group (23.2%). • The proportion of subjects with bone lesions at randomization was higher in the niraparib + AAP group (86.3%) than in the placebo + AAP group (80.6%). • The proportion of participants with visceral disease at randomization was higher in the niraparib + AAP group (24.1%) than in the placebo + AAP group (18.5%). The empirical prognostic model developed by Halabi et al. (2014) was used to calculate the overall risk score for each subject using eight established prognostic factors (opioid use, disease site, ECOG performance status score, LDH, albumin, hemoglobin, alkaline phosphatase, and PSA). As shown in Table 2 below, the median score along with the interquartile range indicates that the risk score was consistently higher in the niraparib + AAP group within the BRCA subgroup, confirming that the imbalance of prognostic factors does not support the niraparib + AAP regimen. This analysis underscores the importance of multivariate analysis adjusted for key prognostic factors.

[0339] Table 2: Summary of Halabi prognostic risk scores Multivariate analysis results Based on SAP, a pre-specified multivariate Cox regression analysis was performed on the overall survival (OS) of the BRCA subgroup. This analysis adjusted for external validation and clinically relevant baseline prognostic factors (Halabi 2014, Guinney 2017, Sartor 2018). The results showed improved OS (HR=0.663; 95% CI: 0.464, 0.947), supporting the use of niraparib + AAP for treatment (see TEFOS08_BRCA in the table below).

[0340] Figure 2 OS forest plots for BRCA subgroups analyzed by predefined subgroups are presented. Results generally and consistently support the niraparib + AAP regimen, with point estimates of HR greater than 1 only in subjects who had previously received taxane-based chemotherapy, had a history of AAP use, had visceral metastases, or had high PSA levels.

[0341] Time to symptom progression (TSP) and time to initiation of cytotoxic chemotherapy (TCC) in the BRCA subgroup Updated analysis of TSP during FA confirmed that, in the BRCA subgroup, subjects treated with niraparib plus AAP showed a consistent and clinically significant improvement in TSP compared to placebo plus AAP (HR=0.562; 95% CI: 0.371, 0.849). The early and widening separation of the Kaplan-Meier curves supports the use of niraparib plus AAP. Figure 3a The median TSP was not reached in the niraparib + AAP group, while the median TSP in the placebo + AAP group was 21.7 months.

[0342] Updated analysis of TCC at FA continued to show delayed TCC in BRCA recipients receiving niraparib + AAP (HR=0.598; 95% CI: 0.387, 0.924). Similar to TSP, the separation of the Kaplan Meier curves appeared earlier and widened over time, supporting the niraparib + AAP group ( Figure 3b The median TCC was not reached in the niraparib + AAP group, while the median TCC in the placebo + AAP group was 28.2 months.

[0343] Table 3: TSP and TCC of BRCA subgroups at FA * The HR estimates are derived from a stratified Cox proportional hazards model.

[0344] ** The p-value is based on the stratified log-rank test.

[0345] The TCC in all HRR populations did not cross the pre-specified significance boundary at FA. However, clinically meaningful improvements were observed.

[0346] Subsequent treatment of prostate cancer in the BRCA subgroup At FA, more BRCA subjects in the placebo + AAP group received subsequent treatment for prostate cancer, compared to fewer in the niraparib + AAP group. Chemotherapy was the most common subsequent treatment received in both treatment groups; subsequent use of PARP inhibitors was more frequent in the placebo + AAP group (Table 4; Table below TEFSUBTX02_BRCA).

[0347] Table 4: Summary of subsequent prostate cancer treatments selected in the BRCA subgroup of cohort 1 By the time of the FA CCO, 180 subjects (80%) in the BRCA subgroup had discontinued treatment. Of these subjects, 146 discontinued treatment due to disease progression: 60 / 113 (53.1%) in the niraparib + AAP group and 86 / 112 (76.8%) in the placebo + AAP group. Among subjects who discontinued study treatment due to disease progression, a higher proportion of subjects treated with placebo + AAP received a PARP inhibitor compared to those treated with niraparib + AAP (niraparib + AAP: 3 / 60 [5.0%]; placebo + AAP: 29 / 86 [33.7%]). The proportion of subjects who received subsequent chemotherapy after discontinuing treatment due to disease progression was similar in both treatment groups (niraparib + AAP: 34 / 60 [56.7%]; placebo + AAP: 51 / 86 [59.3%]), indicating that niraparib + AAP treatment did not prevent subjects with disease progression from receiving subsequent chemotherapy. (See Table TEFSUBTX02PD_BRCA below).

[0348] Patient-reported results in the BRCA subgroup An updated patient-reported outcome analysis in the BRCA subgroups showed that the efficacy benefit of niraparib + AAP was accompanied by a longer time to pain progression.

[0349] In the BRCA subgroup, the median time to clinically significant progression of BPI-SF most severe pain was not reached in subjects receiving niraparib + AAP, compared to 32.2 months in subjects receiving placebo + AAP (HR=0.809; 95% CI: 0.524, 1.249; p=0.3378). In the niraparib + AAP group, the median time to progression of BPI-SF pain interference was not reached, compared to 41.5 months in the placebo + AAP group (HR=0.771; 95% CI: 0.481, 1.234; p=0.2778).

[0350] Cohort 1, Final Safety Analysis (All HRR Populations) All subjects in Cohort 1 who received at least one dose of study treatment were included in the safety analysis. At the FA CCO, the median duration of treatment for subjects randomized to niraparib + AAP in Cohort 1 was 20.2 months, compared to 15.2 months for those randomized to placebo + AAP. The overall safety profile remained consistent with IA2 and the 4-month safety update (4MSU), and no new safety signals were identified due to additional treatment exposure.

[0351] A summary of treatment-emergent adverse events (TEAEs) occurring during the treatment period in Cohort 1 is presented in Table 6. The higher incidence of adverse events (AEs) observed in the niraparib + AAP group remained primarily driven by known hematologic AEs associated with niraparib. The most common TEAEs in the niraparib + AAP group remained unchanged since IA2, and the overall side effect profile of the niraparib + AAP regimen remained manageable. There was a slight numerical increase in grade 3-4 TEAEs and serious adverse events (SAEs), reflecting increased study treatment exposure since IA2 and 4 MSU. Furthermore, the safety profile observed in the BRCA subgroup treated with niraparib + AAP was consistent with the safety profile of the entire HRR population in Cohort 1 (updated tables of adverse event rates and laboratory abnormalities observed in the BRCA subgroups are provided in Table TSFAE07_modified below).

[0352] Table 6: Overall safety characteristics of queue 1 (all HRRs) Definition: AAP = abiraterone acetate plus prednisone; AE = adverse event. a An AE is classified as relevant if the researcher assesses that it is associated with niraparib, abiraterone acetate, or prednisone.

[0353] b The AE that leads to death is based on the AE ending being "fatal".

[0354] c If an adverse event (AE) leads to the discontinuation of niraparib, abiraterone acetate, or prednisone, the AE is counted as a cause of discontinuation of the investigational drug.

[0355] TEAE that led to death In Cohort 1, at FA CCO, 22 subjects (10.4%) in the niraparib + AAP group experienced fatal AEs, compared to 10 subjects (4.7%) in the placebo + AAP group (at IA2, the numbers were 20 [9.4%] in the niraparib + AAP group and 9 [4.3%] in the placebo + AAP group, respectively). Although COVID-19 was the most common fatal TEAE in both treatment groups, no deaths due to COVID-19 have occurred since IA2.

[0356] Adverse events of particular concern In cohort 1, more subjects experienced adverse events of particular concern (AESIs) in the niraparib + AAP group compared to the placebo + AAP group (Table 6). Similar to IA2 and 4MSU, the higher incidence of AESIs in the niraparib + AAP group was primarily driven by hematologic toxicities, which were manageable with dose modification and supportive care, and most subjects were able to continue treatment with niraparib + AAP. The overall incidence of other AESIs was similar to that reported at IA2 and 4MSU, including cardiac disease and hypertension. No cases of MDS or AML were reported in the niraparib + AAP group (in the placebo + AAP group, one subject with a TEAE of AML was observed at IA1).

[0357] Dosage modification In all HRR populations in Cohort 1, more AEs leading to dose modification were observed in the niraparib + AAP group compared to the placebo + AAP group (Table 7). The number of subjects with AEs leading to niraparib dose interruption increased since IA2, reflecting increased study treatment exposure between IA2 and the FA CCO; the most common AEs leading to niraparib dose interruption remained unchanged in the niraparib + AAP group (anemia: 49 [23.1%], followed by thrombocytopenia: 24 [11.3%]). The number of subjects with AEs leading to dose reductions in either niraparib or placebo remained unchanged since IA2, and anemia and thrombocytopenia were again the most common AEs leading to dose reductions in the niraparib + AAP group. Nine additional subjects experienced AEs leading to niraparib or placebo discontinuation at the FA CCO compared to IA2 (7 in the niraparib + AAP group and 2 in the placebo + AAP group); however, most subjects in both groups continued study treatment until disease progression or were still receiving study treatment.

[0358] Table 7: Dosage Modifications and Treatment Discontinuation of Niraparib or Placebo at FA and IA2 Queue 3 Final Analysis Cohort 3 was enrolled after enrollment in Cohorts 1 and 2, and consisted of 95 subjects with HRR gene alterations. All subjects received open-label FDC tablets (niraparib / AA) plus prednisone. Cohort 3 provided clinical experience with the FDC tablet formulation, and no formal hypothesis testing was performed on efficacy. At the FA CCO, 19 BRCA subjects (36.5%) were still receiving study treatment. The most common reason for treatment discontinuation was disease progression (24 subjects [46.2%]); a small number of subjects discontinued treatment due to AEs (6 subjects [11.5%]).

[0359] Overall, the safety profile observed in cohort 3 patients treated with niraparib / AA FDC plus prednisone was consistent with the safety profile of niraparib + AAP SAC in all HRR populations and BRCA subgroups of cohort 1. The median duration of treatment in cohort 3 was 19.5 months, no new safety signals were identified, and the pattern of AE reports observed in cohort 3 patients was similar to that in the niraparib + AAP group of cohort 1.

[0360] in conclusion In the primary analysis (PA-IA1), statistically significant and clinically meaningful improvements were observed in the primary endpoint rPFS in the BRCA subgroup and all HRR populations in cohort 1.

[0361] This final analysis demonstrated a strong trend toward improved overall survival (OS) with niraparib + AAP in the BRCA subgroup (HR=0.788; 95% CI: 0.544, 1.120; p=0.1828), with sustained and clear separation of the Kaplan-Meier curves, despite a higher proportion of patients in the placebo + AAP group receiving subsequent treatment (particularly taxane-based chemotherapy and approved life-extending agents such as PARP inhibitors). These results are further supported by consistent and clinically meaningful improvements in TSP and TCC, clearly demonstrating the benefit of niraparib + AAP as first-line treatment for patients with mCRPC and BRCA alterations.

[0362] An imbalance was found in the assessment of prognostic risk factors between the two treatment groups, supporting the placebo + AAP model (median risk score based on the Halabi et al. model was 0.69 in the placebo + AAP group and 0.75 in the niraparib + AAP group), highlighting the importance of using a multivariate model to adjust for these imbalances. Indeed, prespecified multivariate analyses that adjusted for these imbalances showed a treatment benefit in OS for subjects treated with niraparib + AAP in the BRCA subgroup (HR=0.663; 95% CI: 0.464, 0.947).

[0363] In the BRCA subgroup of cohort 1, consistent and clinically significant improvements were observed in both TSP and TCC, with clear separation of the KM curves for the two endpoints observed early and strengthening with prolonged follow-up. In mCRPC, the benefits observed on these well-validated and highly patient-relevant endpoints were also reflected in patient-reported outcomes; in BRCA-altered subjects treated with niraparib + AAP, a prolonged trend was observed in both the time to clinically significant progression to the most severe pain intensity of BPI-SF and the time to clinically significant progression to pain interference.

[0364] The safety profile of niraparib + AAP at FA was consistent with previous analyses, with no new safety signals observed during longer exposure durations and additional follow-up. Despite a high baseline disease burden in the older population (26.5% of whom were over 75 years old), the niraparib + AAP combination therapy remained tolerable. In all HRR populations and BRCA subgroups in cohort 1, treatment with niraparib + AAP was manageable through dose interruptions, reductions, and supportive care. Most subjects treated with niraparib + AAP were able to continue treatment until disease progression. The safety profile of niraparib / AA FDC formulation + prednisone observed in cohort 3 appeared consistent with that observed in cohort 1.

[0365] In summary, the final analysis results continue to demonstrate a positive benefit-risk ratio in BRCA-mutated mCRPC patients treated with niraparib plus AAP. Efficacy analysis showed a robust trend toward improvement in overall survival (OS) and clinically meaningful improvements in key secondary endpoints TSP and TCC, while overall health-related quality of life was maintained in patients treated with niraparib plus AAP. Updated safety analysis confirmed that niraparib plus AAP is tolerable and its toxicities are manageable. In conclusion, the MAGNITUDE study clearly demonstrates the significant benefit of niraparib plus AAP as first-line treatment for patients with BRCA alterations in mCRPC.

[0366] result Subject and treatment information therapeutic effect Security Example 2 – Drug product label approved by the European Medicines Agency (EMA) Approval Date: April 19, 2023 Appendix I Product Features Summary 1. Drug Name Akeega 50mg / 500mg film-coated tablets Akeega 100mg / 500mg film-coated tablets 2. Qualitative and quantitative compositions Akeega 50mg / 500mg film-coated tablets Each film-coated tablet contains niraparib tosylate monohydrate, equivalent to 50 mg of niraparib, and abiraterone acetate, equivalent to 446 mg of abiraterone.

[0367] Akeega 100mg / 500mg film-coated tablets Each film-coated tablet contains niraparib tosylate monohydrate, equivalent to 100 mg of niraparib, and 500 mg of abiraterone acetate, equivalent to 446 mg of abiraterone.

[0368] Excipients with known effects Each film-coated tablet contains 241 mg of lactose (see Section 4.4). For a complete list of excipients, see Section 6.1.

[0369] 3. Dosage form Film-coated tablets.

[0370] Akeega 50mg / 500mg film-coated tablets Yellow-orange to yellow-brown, oval-shaped, film-coated sheet (22mm×11mm), with "N 50 A" engraved on one side and blank on the other.

[0371] Akeega 100mg / 500mg film-coated tablets Orange, oval, film-coated sheet (22mm×11mm), with "N 100 A" engraved on one side and blank on the other.

[0372] 4. Clinical Matters 4.1 Treatment Indications Akeega was instructed to use prednisone or prednisolone to treat adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1 / 2 mutations (germline and / or somatic mutations) who had no clinical indication for chemotherapy.

[0373] 4.2 Usage and Dosage Treatment with niraparib and abiraterone acetate plus prednisone or prednisolone should be initiated and supervised by a specialist with experience in drug therapy for prostate cancer.

[0374] Before initiating Akeega treatment, a BRCA-positive status must be determined using a validated testing method (see Section 5.1).

[0375] Dosage The recommended starting dose of Akeega is 200 mg / 1,000 mg (two 100 mg niraparib / 500 mg abiraterone acetate tablets) once daily at approximately the same time each day (see “Directions for Administration” below). 50 mg / 500 mg tablets may be used to reduce the dose.

[0376] For patients who have not undergone surgical castration, gonadotropin-releasing hormone (GnRH) analogues should be used for medical castration during treatment.

[0377] Dosage of prednisone or prednisolone Akeega is used daily with 10 mg of prednisone or prednisolone.

[0378] Treatment duration Patients should receive treatment until the disease progresses or unacceptable toxicity occurs.

[0379] Missed dose If you miss a dose of Akeega, prednisone, or prednisolone, take it as soon as possible on the same day and resume your normal schedule the following day. Do not take extra tablets to make up for a missed dose.

[0380] Dosage adjustment for adverse reactions Non-hematological adverse reactions For patients experiencing grade ≥3 non-hematologic adverse reactions, treatment should be interrupted and appropriate medical management should be implemented (see Section 4.4). Akeega treatment should not be restarted until the toxicity symptoms have resolved to grade 1 or baseline levels.

[0381] Hematological adverse reactions For patients experiencing grade ≥3 or intolerable hematologic toxicity, Akeega administration should be interrupted rather than discontinued, and supportive management should be considered. If hematologic toxicity does not recover to an acceptable level within 28 days of the dose interruption period, Akeega should be permanently discontinued.

[0382] Dosage adjustment recommendations for thrombocytopenia and neutropenia are listed in Table 1.

[0383] Subsequent administration of Akeega may be resumed only when toxicity due to thrombocytopenia and neutropenia improves to Grade 1 or resolves to baseline levels. Treatment can be resumed with a lower dose of Akeega 50 mg / 500 mg (2 tablets). For the most common adverse reactions, see Section 4.8.

[0384] For anemia grade ≥3, Akeega should be discontinued and supportive care provided until recovery to grade ≤2. If anemia persists based on clinical judgment, dose reduction (two 50mg / 500mg tablets) should be considered. Dosage adjustment recommendations for anemia are listed in Table 2.

[0385] Hepatotoxicity For patients who develop grade ≥3 hepatotoxicity (elevated alanine aminotransferase [ALT] or aspartate aminotransferase [AST] more than five times the upper limit of normal [ULN]), Akeega treatment should be interrupted and liver function should be closely monitored (see Section 4.4).

[0386] Treatment can only be restarted at a reduced dose level (one regular-strength Akeega tablet, equivalent to 100 mg niraparib / 500 mg abiraterone acetate) after liver function tests have returned to the patient's baseline levels. For patients restarting treatment, serum transaminases should be monitored at least every two weeks for the first three months, and monthly thereafter. If hepatotoxicity recurs at a reduced dose of 100 mg / 500 mg (one tablet) daily, Akeega treatment should be discontinued.

[0387] If a patient experiences severe hepatotoxicity (ALT or AST levels 20 times higher than ULN) while using Akeega, treatment should be permanently discontinued.

[0388] For patients with concurrent elevations of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN, and without biliary obstruction or other causes of the elevation, Akeega should be permanently discontinued (see Section 4.4).

[0389] Recommended monitoring Complete blood counts should be obtained before the start of treatment, weekly for the first month, bi-weekly for the next two months, monthly for the first year thereafter, and then monthly for the remainder of treatment to monitor for any clinically significant changes in hematological parameters (see Section 4.4).

[0390] Serum aminotransferases and total bilirubin should be measured before starting treatment, every two weeks for the first three months of treatment, monthly for the first year thereafter, and then monthly for the duration of treatment. When starting a lower-intensity dose (two tablets) after a dose interruption, liver function should be monitored every two weeks for six weeks before resuming routine monitoring due to the increased risk of abiraterone exposure (see Section 5.2). Serum potassium should be monitored monthly for the first year of treatment, and then monthly for the duration of treatment (see Section 4.4).

[0391] Blood pressure should be monitored weekly for the first two months, monthly for the first year, and then monthly for the duration of treatment.

[0392] For patients with pre-existing hypokalemia or who develop hypokalemia during Akeega treatment, consider maintaining their potassium levels at ≥4.0 mM.

[0393] Special populations elderly No dose adjustment is required for elderly patients (see Section 5.2).

[0394] Liver function impairment No dose adjustment is required for patients with pre-existing mild hepatic impairment (Child-Pugh Class A). There are no clinical safety and efficacy data regarding multiple doses of Akeega in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). Dose adjustments cannot be predicted. Akeega should be carefully evaluated in patients with moderate hepatic impairment, and the benefits should clearly outweigh the potential risks (see Sections 4.4 and 5.2). Akeega is contraindicated in patients with severe hepatic impairment (see Sections 4.3, 4.4, and 5.2).

[0395] Kidney damage No dose adjustment is required for patients with mild to moderate renal impairment. However, for patients with moderate renal impairment, close monitoring for safety events is necessary due to the potential increase in niraparib exposure. There are no data regarding the use of Akeega in patients with severe renal impairment or end-stage renal disease undergoing hemodialysis. Akeega should only be used in patients with severe renal impairment when the benefits outweigh the potential risks, and patients should be carefully monitored for renal function and adverse events (see Sections 4.4 and 5.2).

[0396] Pediatric population Akeega has no relevant use in the pediatric population.

[0397] Application method Akeega is for oral use.

[0398] The tablets must be taken as a single dose once daily. Akeega should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal (see Section 5.2). For optimal absorption, Akeega tablets must be swallowed whole with water and should not be broken, crushed, or chewed.

[0399] Precautions to be taken before handling or applying the product Pregnant women or women who may become pregnant should wear gloves when handling tablets (see Section 6.6).

[0400] 4.3 Contraindications Hypersensitivity to the active substance or any of the excipients listed in Section 6.1.

[0401] A woman who is pregnant or may become pregnant (see Section 4.6).

[0402] Severe liver dysfunction [Child-Pugh C (see Sections 4.2, 4.4 and 5.2)].

[0403] Akeega plus prednisone or prednisolone is contraindicated in combination with Ra-223 treatment.

[0404] 4.4 Special Warnings and Precautions Hematological adverse reactions Hematological adverse reactions (thrombocytopenia, anemia, and neutropenia) have been reported in patients treated with Akeega (see Section 4.2).

[0405] It is recommended that complete blood counts be tested weekly during the first month of treatment, bi-weekly for the next two months, monthly for the first year thereafter, and then monthly for the remainder of treatment to monitor for any clinically significant changes in any hematological parameters (see Section 4.2).

[0406] Based on individual laboratory values, weekly monitoring may be required in the second month.

[0407] Akeega should be discontinued if the patient develops severe, persistent hematologic toxicity (including pancytopenia) that does not improve within 28 days of treatment interruption.

[0408] Because of the risk of thrombocytopenia, patients taking Akeega should use other medications known to reduce platelet counts with caution (see Section 4.8).

[0409] When starting a lower-intensity dose (two tablets) after a dose interruption due to hematologic adverse reactions, liver function should be monitored every two weeks for six weeks until regular monitoring is resumed (see Section 4.2) due to the increased risk of abiraterone exposure (see Section 5.2).

[0410] hypertension Akeega may cause hypertension; pre-existing hypertension should be adequately controlled before starting Akeega treatment. During Akeega treatment, blood pressure should be monitored weekly for at least the first two months, monthly for the first year thereafter, and then monthly thereafter.

[0411] Hypokalemia, fluid retention, and cardiovascular adverse reactions due to mineralocorticoid overdose: Akeega may cause hypokalemia and fluid retention due to elevated mineralocorticoid levels caused by CYP17 inhibition (see Section 4.8) (see Section 5.1). Concomitant use of corticosteroids to inhibit adrenocorticotropic hormone (ACTH) drive can reduce the incidence and severity of these adverse reactions. Caution should be exercised when treating patients whose underlying health conditions may be exacerbated by hypokalemia (e.g., patients using cardiac glycosides) or fluid retention (e.g., patients with heart failure, severe or unstable angina, recent myocardial infarction or ventricular arrhythmias, and patients with severe renal impairment). QT interval prolongation has been observed in patients who developed hypokalemia associated with Akeega treatment. Hypokalemia and fluid retention should be corrected and controlled.

[0412] Heart failure should be treated and cardiac function optimized before treating patients at significant risk of congestive heart failure (e.g., a history of heart failure or cardiac events such as ischemic heart disease). Fluid retention (weight gain, peripheral edema) and other signs and symptoms of congestive heart failure should be monitored every two weeks for the first three months, then monthly thereafter, with any abnormalities corrected. Akeega should be used with caution in patients with a history of cardiovascular disease.

[0413] The management of cardiac risk factors (including hypertension, dyslipidemia, and diabetes) in patients receiving Akeega treatment should be optimized, and these patients should be monitored for signs and symptoms of cardiac disease.

[0414] Abiraterone acetate (a component of Akeega) increases mineralocorticoid levels and carries a risk of cardiovascular events. Excessive mineralocorticoids can cause hypertension, hypokalemia, and fluid retention. Previous androgen deprivation therapy (ADT) exposure and advanced age are additional risk factors for cardiovascular morbidity and mortality. The MAGNITUDE study excluded patients with clinically significant heart disease, evidence including myocardial infarction, arterial and venous thrombosis within the past six months, severe or unstable angina, or NYHA class II to IV heart failure or a cardiac ejection fraction <50%. Patients with a history of heart failure should be clinically optimized and given appropriate symptom management. Discontinuation of Akeega should be considered if a clinically significant decline in cardiac function occurs.

[0415] Infect In the MAGNITUDE study, patients treated with Akeega experienced a higher frequency of serious infections, including COVID-19 infections with fatal outcomes. Patients should be monitored for signs and symptoms of infection. Serious infections may occur in the absence of neutropenia and / or leukopenia.

[0416] Pulmonary embolism (PE) In the MAGNITUDE study, the reported frequency of PE cases was higher in patients treated with Akeega than in the control group. Patients with a history of PE or venous thrombosis may face a higher risk of recurrence. Patients should be monitored for clinical signs and symptoms of PE. If clinical features of PE appear, the patient should be promptly evaluated and appropriate treatment administered.

[0417] Posterior reversible encephalopathy syndrome (PRES) Preeclampsia (PRES) is a rare, reversible neurological disorder that can present with rapidly evolving symptoms, including seizures, headache, altered mental status, visual disturbances or cortical blindness, with or without associated hypertension. Diagnosis of PRES requires confirmation via brain imaging, preferably magnetic resonance imaging (MRI).

[0418] Previous reports have shown that patients with ovarian cancer who received 300 mg niraparib (a component of Akeega) as monotherapy experienced PRES. In the MAGNITUDE study, no cases of PRES were reported in prostate cancer patients treated with 200 mg niraparib.

[0419] If PRES occurs, Akeega treatment should be permanently discontinued, and appropriate medical management should be implemented.

[0420] Hepatotoxicity and liver function impairment Hepatotoxicity has been identified as a significant risk associated with abiraterone acetate (a component of Akeega). The mechanisms of hepatotoxicity of abiraterone acetate are not fully understood. Patients with moderate to severe hepatic impairment (NCI classification) and those with Child-Turcotte-Pugh class B and C were excluded from Akeega combination studies.

[0421] In the MAGNITUDE study and all combined clinical studies, the risk of hepatotoxicity was mitigated by excluding patients with baseline hepatitis or significantly abnormal liver function tests (serum total bilirubin >1.5×ULN or direct bilirubin >1×ULN, and AST or ALT >3×ULN).

[0422] Significant elevations of liver enzymes leading to treatment interruption or cessation have occurred in clinical studies, although these are uncommon (see Section 4.8). Serum aminotransferase and total bilirubin levels should be measured before starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. When starting a lower-intensity dose (two tablets) after a dose interruption, liver function should be monitored every two weeks for six weeks until regular monitoring resumes, due to the increased risk of abiraterone exposure (see Section 5.2). Serum transaminases should be measured immediately if clinical signs or symptoms suggestive of hepatotoxicity appear. Patients with elevated aminotransferases treated with Akeega should be managed immediately by interrupting treatment. If ALT or AST increases by more than 5 times the ULN at any time, Akeega treatment should be interrupted and liver function closely monitored. Treatment can only be restarted at a reduced dose level after liver function tests have returned to the patient's baseline levels (see Section 4.2).

[0423] For patients with ALT or AST elevations >20×ULN, treatment should be permanently discontinued. For patients with concurrent elevations of ALT >3×ULN and total bilirubin >2×ULN, and without biliary obstruction or other causes of the concurrent elevations, treatment should be permanently discontinued.

[0424] If a patient experiences severe hepatotoxicity (ALT or AST being 20 times higher than ULN) at any time during treatment, Akeega treatment should be permanently discontinued.

[0425] Patients with active or symptomatic viral hepatitis were excluded from the clinical study; therefore, there is no data to support the use of Akeega in this population.

[0426] Moderate hepatic impairment (Child-Pugh B or any AST and TB > 1.5 × 3 × ULN) has been shown to increase systemic exposure to abiraterone and niraparib (see Section 5.2). There are no clinical safety and efficacy data regarding multiple doses of Akeega in patients with moderate or severe hepatic impairment. Akeega should be carefully evaluated in patients with moderate hepatic impairment, and its benefits should clearly outweigh the potential risks (see Sections 4.2 and 5.2). Akeega should not be used in patients with severe hepatic impairment (see Sections 4.2, 4.3, and 5.2).

[0427] hypoglycemia There have been reports of hypoglycemia occurring when abiraterone acetate (a component of Akeega) was administered in combination with prednisone or prednisolone to patients with pre-existing diabetes who were receiving pioglitazone or repaglinide (metabolized via CYP2C8) (see Section 4.5). Therefore, blood glucose levels should be monitored in patients with diabetes.

[0428] Myelodysplastic syndrome / acute myeloid leukemia (MDS / AML) In ovarian cancer research, there have been reports of MDS / AML (including cases with fatal outcomes) in patients treated with 300 mg niraparib (a component of Akeega).

[0429] No cases of MDS / AML were observed in patients treated with 200 mg niraparib and 1,000 mg abiraterone acetate plus prednisone or prednisolone.

[0430] For suspected MDS / AML or long-term hematologic toxicities that do not improve with treatment interruption or dose reduction, patients should be referred to a hematologist for further evaluation. If MDS and / or AML is confirmed, Akeega therapy should be permanently discontinued, and the patient should be treated appropriately.

[0431] Corticosteroid discontinuation and stress coverage If a patient discontinues prednisone or prednisolone, caution is advised and adrenal insufficiency should be monitored. If Akeega is continued after discontinuation of corticosteroids, the patient should be monitored for symptoms of mineralocorticoid overdose (see information above).

[0432] For patients who are receiving prednisone or prednisolone treatment and are experiencing abnormal stress, the dose of corticosteroids may need to be increased before, during, and after the stressful event.

[0433] Bone density Men with metastatic advanced prostate cancer may experience decreased bone mineral density. Using abiraterone acetate (a component of Akeega) in combination with glucocorticoids may exacerbate this effect.

[0434] Combining with radium (Ra)-223 dichloride increases fracture and mortality rates. The combination of Akeega with prednisone or prednisolone with Ra-223 is prohibited (see Section 4.3) because clinical studies using abiraterone acetate (a component of Akeega) have shown an increased risk of fractures and a trend toward higher mortality in asymptomatic or mildly symptomatic prostate cancer patients.

[0435] It is recommended that at least five days follow the last administration of Akeega in combination with prednisone or prednisolone before initiating subsequent Ra-223 treatment.

[0436] hyperglycemia The use of glucocorticoids may increase hyperglycemia, therefore blood glucose levels should be measured frequently in diabetic patients.

[0437] Skeletal muscle effect No cases of myopathy or rhabdomyolysis were observed in patients treated with Akeega. In studies of abiraterone acetate (a component of Akeega) monotherapy, most cases occurred within the first six months of treatment and resolved upon discontinuation of abiraterone acetate. Caution is advised for patients being treated concurrently with medications known to be associated with myopathy / rhabdomyolysis.

[0438] Interactions with other drugs Strong CYP3A4 inducers should be avoided during treatment unless there is no alternative treatment, as there is a risk of reduced abiraterone exposure (see Section 4.5).

[0439] lactose and sodium This medication contains lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

[0440] Each dose of this drug contains less than 1 mmol (23 mg) of sodium, which is essentially "sodium-free".

[0441] 4.5 Interactions with other drugs and other forms of interaction Pharmacokinetic Interactions There have been no clinical studies evaluating drug interactions using Akeega. Interactions identified in studies of the individual components of Akeega (niraparib or abiraterone acetate) determine potential interactions with Akeega.

[0442] Effects of other medications on niraparib or abiraterone acetate CYP3A4 inducers and inhibitors Abiraterone is a CYP3A4 substrate. In a clinical study in healthy subjects, after prior treatment with a potent CYP3A4 inducer rifampin (600 mg daily for six days), a single dose of abiraterone acetate 1,000 mg was administered. The mean plasma AUC of abiraterone was... ∞ Reduced by 55%. Strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort [Hypericumper foratum]) should be avoided during treatment with Akeega unless no alternative treatment is available (see Section 4.4).

[0443] In another clinical study of healthy subjects, co-administration with the potent CYP3A4 inhibitor ketoconazole had no clinically meaningful effect on the pharmacokinetics of abiraterone.

[0444] Effects of niraparib or abiraterone acetate on other medications CYP2D6 substrate Abiraterone is a CYP2D6 inhibitor. In a clinical study determining the effect of abiraterone acetate plus prednisone (AAP) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan increased by approximately 2.9-fold. The AUC of dextromethorphan's active metabolite, dextromethorphan, is also shown. 24 This represents an increase of approximately 33%. Reduction of the dosage of drugs metabolized by CYP2D6 and with a narrow therapeutic index should be considered. Examples of drugs metabolized by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone, and tramadol.

[0445] CYP2C8 substrate Abiraterone is a CYP2C8 inhibitor. In a clinical study in healthy subjects, when pioglitazone (a CYP2C8 substrate) was co-administered with a single dose of 1,000 mg abiraterone acetate, the AUC of pioglitazone increased by 46%, while the AUCs of its active metabolites M-III and M-IV each decreased by 10%. If a CYP2C8 substrate with a narrow therapeutic index is used concomitantly with akeega, patients should be monitored for signs of substrate-related toxicity due to the abiraterone acetate component. Examples of drugs metabolized by CYP2C8 include pioglitazone and repaglinide (see Section 4.4).

[0446] Pharmacodynamic Interactions The interaction between Akeega and vaccines or immunosuppressants has not been studied.

[0447] Data on the combination of niraparib and cytotoxic drugs is limited. Caution should be exercised when using Akeega in combination with live or attenuated vaccines, immunosuppressants, or other cytotoxic drugs.

[0448] Use with products known to prolong the QT interval Because androgen deprivation therapy may prolong the QT interval, caution is advised when using Akeega in combination with drugs known to prolong the QT interval or drugs that can induce torsades de pointes (such as class IA (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs, methadone, moxifloxacin, antipsychotics, etc.).

[0449] Used with spironolactone Spironolactone binds to androgen receptors and may increase prostate-specific antigen (PSA) levels. It is not recommended for use with Akeega (see Section 5.1).

[0450] 4.6 Fertility, Pregnancy and Lactation Contraception for women of childbearing age / men and women It is unclear whether components of Akeega or its metabolites are present in semen.

[0451] During Akeega treatment and within four months of the last dose: • If the patient has sexual intercourse with a pregnant woman, a condom should be used.

[0452] • If the patient has sexual intercourse with a woman of childbearing age, a condom and another effective method of contraception should be used.

[0453] Animal studies have shown reproductive toxicity (see Section 5.3).

[0454] pregnancy Akeega is not applicable to women (see Section 4.3).

[0455] There are no data on the use of Akeega in pregnant women. Based on the mechanisms of action of the two components and animal studies of abiraterone acetate, Akeega has been found to pose a potential risk of fetal harm. No animal developmental and reproductive toxicology studies have been conducted on niraparib (see Section 5.3).

[0456] Breastfeeding Akeega is not suitable for women.

[0457] Fertility There are no clinical data on the effects of Akeega on fertility. In animal studies, niraparib or abiraterone acetate reduced male fertility, but these effects were reversible upon discontinuation of treatment (see Section 5.3).

[0458] 4.7 Impact on the ability to drive and operate machinery Akeega has a moderate effect on the ability to drive or operate machinery. Patients taking Akeega may experience weakness, fatigue, dizziness, or difficulty concentrating. Caution should be exercised when driving or operating machinery.

[0459] 4.8 Adverse Effects Security Features Summary The overall safety profile of Akeega is based on data from a phase 3, randomized, double-blind, placebo-controlled study (MAGNITUDE cohort 1, N=212). The most common adverse events (incidence >10%) of all grades in the Nirapaniga AAP group were: anemia (50.0%), hypertension (33.0%), constipation (33.0%), fatigue (29.7%), nausea (24.5%), thrombocytopenia (23.1%), dyspnea (17.9%), back pain (17.0%), decreased appetite (15.6%), neutropenia (15.1%), arthralgia (15.1%), vomiting (14.6%), hypokalemia (13.7%), dizziness (12.7%), insomnia (11.3%), hyperglycemia (11.8%), and urinary tract infection (10.4%). The most frequently observed grade 3 to 4 adverse reactions were anemia (30.2%), hypertension (15.6%), thrombocytopenia (7.5%), neutropenia (6.6%), and elevated serum alkaline phosphatase (5.7%).

[0460] Adverse reactions list made into a table Adverse reactions observed during the clinical study are listed below by frequency category. The frequency categories are defined as follows: very common (≥1 / 10); common (≥1 / 100 to <1 / 10); occasional (≥1 / 1,000 to <1 / 100); rare (≥1 / 10,000 to <1 / 1,000); very rare (<1 / 10,000); and unknown (frequency cannot be estimated based on available data).

[0461] Within each frequency group, adverse effects are presented in descending order of severity.

[0462] Description of the selected adverse reactions Hematologic toxicity Hematologic toxicities (anemia, thrombocytopenia, and neutropenia), including laboratory test results, are the most common adverse reactions attributed to niraparib (a component of Akeega). These toxicities typically occur within the first two months of treatment, with the incidence decreasing over time.

[0463] In the MAGNITUDE and other Akeega studies, the following hematological parameters were included as inclusion criteria: absolute neutrophil count (ANC) ≥1,500 cells / μL; platelet count ≥100,000 cells / μL and hemoglobin ≥9 g / dL. Hematological adverse reactions were managed through laboratory monitoring and dose modification (see Sections 4.2 and 4.4).

[0464] anemia In the MAGNITUDE study, anemia was the most common adverse reaction (50.0%) and the most frequently observed grade 3 to 4 event (30.2%). Anemia occurred relatively early in the treatment course (median time to onset was 59 days). In the MAGNITUDE study, 22.6% of patients experienced dose interruption, and 13.7% experienced dose reduction. 27% of patients received at least one anemia-related transfusion. Anemia led to a relatively small number of patients (2.4%) discontinuing treatment.

[0465] Thrombocytopenia In the MAGNITUDE study, 23.1% of treated patients reported thrombocytopenia, while 7.5% experienced grade 3 to 4 thrombocytopenia. The median time from first dose to first occurrence was 56 days. In the MAGNITUDE study, thrombocytopenia was managed through dose modification (discontinuation 10.8%, reduction 2.8%) and platelet transfusion when appropriate (2.4%) (see Section 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.4% of patients experienced non-life-threatening bleeding events.

[0466] Neutropenia In the MAGNITUDE study, 15.1% of patients experienced neutropenia, with 6.6% reporting grade 3 to 4 neutropenia. The median time from first dose to first report of neutropenia was 54 days. Neutropenia led to treatment discontinuation in 6.6% of patients and dose reduction in 1.4%. No treatment was discontinued due to neutropenia. In the MAGNITUDE study, 0.9% of patients had co-infections.

[0467] hypertension Hypertension was an adverse effect of both components of Akeega. Patients with uncontrolled hypertension (persistent systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) were excluded from all combination studies. Hypertension was reported in 33% of patients, with 15.6% being grade ≥3. The median time to hypertension was 60.5 days. Hypertension was controlled with adjunctive medication products.

[0468] Patients should have their blood pressure controlled before starting Akeega and should have their blood pressure monitored during treatment (see Section 4.4).

[0469] Heart events In the MAGNITUDE study, the incidence of TEAEs (all grades) of cardiac disease was similar in both groups except for arrhythmia categories. AEs were observed in 13.7% of patients in the nirapaniga AAP group, compared to 7.6% in the placebo plus AAP group (see Section 4.4). The higher frequency of arrhythmias was primarily due to low-grade palpitations, tachycardias, and atrial arrhythmias.

[0470] The median time to onset of arrhythmic events was 105 days in the nirapaniga AAP group and 262 days in the placebo plus AAP group. Arrhythmic events were resolved in 62% of patients in the nirapaniga AAP group and in 63% of subjects in the placebo plus AAP group.

[0471] The incidence of heart failure, acute heart failure, chronic heart failure, and congestive heart failure was 2.4% in the nirapaniga AAP group, compared to 1.9% in the placebo plus AAP group. The median time to onset of heart failure AESI was 206 days in the nirapaniga AAP group and 83 days in the placebo plus AAP group. Heart failure events were resolved in 20% of patients in the nirapaniga AAP group and 25% of patients in the placebo plus AAP group.

[0472] The incidence of ischemic heart disease grouping terms (including the preferred terms angina, acute myocardial infarction, acute coronary syndrome, unstable angina, and coronary atherosclerosis) was 4.2% in the nirapaniga AAP group and 4.3% in the placebo plus AAP group. The median time to onset of ischemic heart disease AESI was 538 days in the nirapaniga AAP group and 257 days in the placebo plus AAP group. Ischemic heart disease events resolved in 78% of patients in both groups.

[0473] Hepatotoxicity In the MAGNITUDE study, the overall incidence of hepatotoxicity was similar in the nirapanib plus AAP group (12.7%) and the placebo plus AAP group (12.8%) (see Sections 4.2 and 4.4). Most of these events were low-grade transaminase elevations. Grade 3 events occurred in 1.4% of patients, and a Grade 4 event occurred in only one patient (0.5%). The incidence of severe adverse events (SAEs) was also 0.9%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 34 days. Hepatotoxicity was managed by dose interruption in 0.9% of patients and by dose reduction in 0.5%. In the MAGNITUDE study, 0.5% of patients discontinued treatment due to hepatotoxicity.

[0474] Pediatric population Akeega has not yet been studied in pediatric patients.

[0475] Report of suspected adverse reactions Reporting suspected adverse reactions after drug authorization is important. It allows for continuous monitoring of the benefit / risk balance of the drug. Healthcare professionals are required to report any suspected adverse reactions listed in Appendix V via the national reporting system.

[0476] 4.9 Drug Overdose There is no specific treatment for Akeegare overdose. In case of overdose, the physician should take general supportive measures and treat the patient symptomatically, including monitoring for signs and symptoms of cardiac arrhythmias, hypokalemia, and fluid retention. Liver function should also be assessed.

[0477] 5. Pharmacological characteristics 5.1 Pharmacodynamic properties Drug therapy classification: Antitumor drugs, other antitumor drugs, ATC code: L01XK Mechanism of action Akeega is a combination of niraparib (a poly(ADP-ribose) polymerase (PARP) inhibitor) and abiraterone acetate (a prodrug of abiraterone) (a CYP17 inhibitor) that targets two oncogenic dependencies in patients with mCRPC and HRR gene mutations.

[0478] Nirapani Niraparib is an inhibitor of poly(ADP-ribose) polymerases (PARP) (PARP-1 and PARP-2), which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzyme activity and increased formation of PARP-DNA complexes, leading to DNA damage, apoptosis, and cell death.

[0479] Abiraterone acetate Abiraterone acetate is converted in vivo to abiraterone, an inhibitor of androgen biosynthesis. Specifically, abiraterone selectively inhibits 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is essential for androgen biosynthesis in these tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to the testosterone precursors DHEA and androstenedione via 17α-hydroxylation and cleavage of the C17,20 bond. Inhibition of CYP17 also leads to increased production of mineralocorticoids by the adrenal glands (see Section 4.4).

[0480] Androgen-sensitive prostate cancer responds to treatments that lower androgen levels. Androgen deprivation therapies, such as treatment with luteinizing hormone-releasing hormone (LHRH) analogs or orchiectomy, reduce androgen production in the testes but do not affect androgen production in the adrenal glands or tumors. When combined with LHRH analogs (or orchiectomy), abiraterone treatment lowers serum testosterone to undetectable levels (using commercially available assays).

[0481] Pharmacodynamic effects Abiraterone acetate Abiraterone lowers serum testosterone and other androgens to levels lower than those achieved with LHRH analogues alone or by orchiectomy. This is due to the selective inhibition of the CYP17 enzyme, which is required for androgen biosynthesis.

[0482] Clinical efficacy and safety First-line treatment for patients with BRCA 1 / 2 mutation mCRPC The efficacy of Akeega was established in the randomized, placebo-controlled, multicenter phase 3 clinical trial MAGNITUDE (study 64091742PCR3001) in patients with mCRPC.

[0483] MAGNITUDE was a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the combination of niraparib (200 mg) and abiraterone acetate (1,000 mg) plus prednisone (10 mg) daily versus standard AAP therapy. Efficacy data were based on cohort 1, which included 423 patients with mCRPC carrying a specific HRR gene mutation who were randomized (1:1) to receive either daily oral niraparib plus AAP (N=212) or placebo plus AAP (N=211). Treatment continued until disease progression, unacceptable toxicity, or death.

[0484] Patients with mCRPC who have not received prior systemic therapy (excluding short-term prior AAP (maximum 4 months)) and are currently receiving ADT are eligible. All patients' plasma, blood, and / or tumor tissue samples were tested using validated next-generation sequencing assays to determine germline and / or somatic HRR gene mutation status. A total of 225 subjects carrying BRCA1 / 2 mutations were enrolled in the study (113 received Akeega). An additional 198 patients carrying non-BRCA1 / 2 mutations (ATM, CHEK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) were enrolled in the study (99 received Akeega).

[0485] The primary endpoint was radiographic progression-free survival (rPFS) determined by blinded independent central imaging (BICR) review based on the Evaluation Criteria for Treatment of Solid Tumors (RECIST) 1.1 (soft tissue and tissue lesions) and the Prostate Cancer Working Group-3 (PCWG-3) criteria (bone lesions). Time to symptom progression (TSP), time to cytotoxic chemotherapy (TCC), and overall survival (OS) were included as secondary efficacy endpoints.

[0486] In all HRR populations, the primary efficacy outcome at a median follow-up of 18.6 months showed a statistically significant improvement in rPFS as assessed by BICR, HR=0.729 (95% CI: 0.556, 0.956; p=0.0217).

[0487] Table 4 summarizes the demographic and baseline characteristics of BRCA patients enrolled in cohort 1 of the MAGNITUDE study. The median PSA at diagnosis was 41.07 ug / L (range 01-12080). At study enrollment, all patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1. All patients who had not previously undergone orchiectomy continued background androgen deprivation therapy with GnRH analogs.

[0488] In the primary analysis, a statistically significant improvement in BICR-assessed rPFS was observed in BRCA patients treated with niraparib plus AAP compared to those treated with placebo plus AAP. Key efficacy outcomes in the BRCA population are presented in Table 5. The Kaplan-Meier curves for BICR-assessed rPFS in the BRCA population are shown in Table 5. Figure 4 As shown in the image.

[0489] Pediatric population The European Medicines Agency has exempted the requirement to submit results from studies of Akeega in all pediatric subgroups of prostate cancer. For information on pediatric use, see Section 4.2.

[0490] 5.2 Pharmacokinetic Characteristics The co-administration of niraparib and abiraterone had no effect on the exposure of their respective components. Compared to the exposure from monotherapy, the AUC and C of niraparib and abiraterone were significantly lower when administered as standard strength (100 mg / 500 mg) film-coated tablets or as a combination of the components, respectively. max They are comparable.

[0491] absorb Akeega In patients with mCRPC, the median time to reach maximum plasma concentration of niraparib was 3 hours and that of abiraterone was 1.5 hours after administration of multiple doses of Akeega tablets under fasting and modified fasting conditions.

[0492] In a relative bioavailability study, the maximum C value of abiraterone was observed in 67 patients with mCRPC treated with lower-intensity film-coated tablets of abiraterone (2×50mg / 500mg). max ) and total (AUC) 0-72h The exposures were 33% and 22% higher, respectively, than those in patients (n=67) treated with either monotherapy (100 mg niraparib capsules and 4 × 250 mg abiraterone acetate tablets) (see Section 4.2). The inter-subject variability (%CV) of exposures was 80.4% and 72.9%, respectively. Niraparib exposures were comparable between Akeega's lower-intensity film-coated tablets and monotherapy.

[0493] Nirapani Niraparib has an absolute bioavailability of approximately 73%. Niraparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with drugs that inhibit these transporters is low.

[0494] Abiraterone acetate Abiraterone acetate is rapidly converted to abiraterone in vivo (see Section 5.1).

[0495] Compared with administration on an empty stomach, administration of abiraterone acetate with food resulted in a mean systemic exposure of abiraterone that was up to 10-fold (AUC) and up to 17-fold (CUC) higher. max The specific risk depends on the fat content of the diet. Given the normal variability in dietary content and composition, taking abiraterone acetate with food carries the potential risk of highly variable exposure. Therefore, abiraterone acetate should not be taken with food.

[0496] distributed Based on population pharmacokinetic analysis, the apparent volumes of distribution of niraparib and abiraterone were 1,117 L and 25,774 L, respectively, indicating extensive extravascular distribution.

[0497] Nirapani Niraparib is moderately bound to proteins (83.0%) in human plasma, primarily to serum albumin.

[0498] Abiraterone acetate 14 C-Abiraterone has a plasma protein binding rate of 99.8% in human plasma.

[0499] Biotransformation Nirapani Niraparib is primarily metabolized by carboxylesterase (CE) to form the major inactive metabolite M1. In a mass balance study, M1 and M10 (which subsequently forms M1 glucuronide) were the major circulating metabolites. At relevant niraparib concentrations, the potential for inhibition of CYP3A4 at intestinal levels has not been established. Niraparib weakly induces CYP1A2 at high concentrations in vitro.

[0500] Abiraterone acetate Oral administration 14 Following C-abiraterone acetate capsule encapsulation, abiraterone acetate is hydrolyzed by CE to abiraterone, which then undergoes metabolism primarily in the liver, including sulfation, hydroxylation, and oxidation. Abiraterone is a substrate of CYP3A4 and sulfonyltransferase 2A1 (SULT2A1). The majority of circulating radioactivity (approximately 92%) is present in the form of abiraterone metabolites. Of the 15 detectable metabolites, the two major metabolites, abiraterone sulfate and N-oxide abiraterone sulfate, each account for approximately 43% of the total radioactivity. Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8 (see Section 4.5).

[0501] eliminate Akeega Based on population pharmacokinetic analysis of mCRPC subjects, the mean t-strength (t) of niraparib and abiraterone during combination administration was... ½ The apparent CL / F of Nirapani and Abiraterone are approximately 62 hours and 20 hours, respectively, and 16.7 L / h and 1673 L / h, respectively.

[0502] Nirapani Niraparib is primarily eliminated via the hepatobiliary and renal pathways. A single oral dose of 300 mg is administered. 14Following niraparib administration, an average of 86.2% (range 71% to 91%) of the dose was recovered in urine and feces over 21 days. Radioactive recovery in urine accounted for 47.5% (range 33.4% to 60.2%) of the dose, and in feces, 38.8% (range 28.3% to 47.0%). In pooled samples collected over six days, 40.0% of the dose was recovered in urine, primarily as metabolites; and 31.6% was recovered in feces, primarily as unchanged niraparib. Metabolite M1 is a substrate for multidrug and toxin efflux proteins (MATE) 1 and 2.

[0503] Abiraterone acetate Oral administration 14 Following administration of 1,000 mg of C-abiraterone acetate, approximately 88% of the radioactive dose was recovered in feces, and approximately 5% in urine. The main compounds present in feces were uncontaminated abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

[0504] Effects of niraparib or abiraterone on transport proteins Niraparib weakly inhibits P-gp, with an IC50 of 161 μM. Niraparib is an inhibitor of BCRP, organic cation transporter 1 (OCT1), MATE-1, and 2, with IC50 values ​​of 5.8 μM, 34.4 μM, 0.18 μM, and ≤0.14 μM, respectively. Abiraterone's major metabolites, abiraterone sulfate and N-oxide abiraterone sulfate, have been shown to inhibit the hepatic uptake transporter organic anion transporter polypeptide 1B1 (OATP1B1). Therefore, plasma exposure of the drug eliminated via OATP1B1 may be increased. No clinical data are available to confirm interactions based on the transporter OATP1B1.

[0505] Special populations Liver function impairment Based on population pharmacokinetic analysis of clinical study data on prostate cancer patients receiving niraparib monotherapy or niraparib / AA combination therapy, mild hepatic impairment (NCI-ODWG criteria, n=231) did not affect niraparib exposure.

[0506] In a clinical study of cancer patients classified according to the degree of liver function impairment using the NCI-ODWG criteria, the AUC of niraparib in patients with moderate hepatic impairment (n=8) after a single dose of 300 mg was [data missing]. inf Niraparib AUC in patients with normal liver function (n=9) inf 1.56 times (90% CI: 1.06 to 2.30).

[0507] The pharmacokinetics of abiraterone were examined in subjects with pre-existing mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh A and B, respectively) and 8 healthy controls. Following a single oral dose of 1,000 mg, systemic exposure to abiraterone increased by approximately 1.11-fold and 3.6-fold in subjects with pre-existing mild and moderate hepatic impairment, respectively.

[0508] In another study, the pharmacokinetics of abiraterone were examined in subjects with pre-existing severe hepatic impairment (N=8) (Child-Pugh C grade) and 8 healthy controls with normal hepatic function. Compared to subjects with normal hepatic function, subjects with severe hepatic impairment showed an approximately 7-fold increase in abiraterone AUC and a 1.8-fold increase in free drug fraction. There is no clinical experience with the use of akeega in patients with moderate to severe hepatic impairment (see Section 4.2).

[0509] Kidney damage Population pharmacokinetic analysis based on clinical study data of prostate cancer patients receiving niraparib monotherapy or niraparib / AA combination therapy showed that, compared with individuals with normal renal function, patients with mild (creatinine clearance 60 to 90 mL / min, n=337) and moderate (creatinine clearance 30 to 60 mL / min, n=114) renal impairment had slightly reduced niraparib clearance (up to 13% increased exposure in mild impairment and 13% to 40% increased exposure in moderate impairment).

[0510] The pharmacokinetics of abiraterone were compared between 8 patients with end-stage renal disease on a stable hemodialysis regimen and 8 matched control subjects with normal renal function. A single oral dose of 1,000 mg did not increase systemic exposure of abiraterone in dialysis-bound end-stage renal disease subjects. There is no clinical experience with the use of abiraterone in patients with severe renal impairment (see Section 4.2).

[0511] Weight, age and race Population pharmacokinetic analysis based on clinical study data of prostate cancer patients receiving niraparib or abiraterone acetate monotherapy or combination therapy: • Body weight has no clinically meaningful effect on exposure to niraparib (weight range: 43.3 kg to 165 kg) and abiraterone (weight range: 56.0 kg to 135 kg).

[0512] • Age had no significant effect on the pharmacokinetics of niraparib (age range 45 to 90 years) and abiraterone (age range 19 to 85 years).

[0513] • There is insufficient data to draw conclusions regarding the effects of ethnicity on the pharmacokinetics of niraparib and abiraterone.

[0514] Pediatric population No studies have been conducted to investigate the pharmacokinetics of Akeega in pediatric patients.

[0515] 5.3 Preclinical safety data Akeega Non-clinical studies of Akeega have not yet been conducted. Non-clinical toxicology data are based on results from individual studies of niraparib and abiraterone acetate.

[0516] Nirapani In vitro, niraparib inhibits dopamine transporters at concentrations below human exposure levels. In mice, a single dose of niraparib increased intracellular levels of dopamine and its metabolites in the cortex. Reduced spontaneous activity was observed in one of two single-dose studies in mice. The clinical relevance of these findings is unclear. In repeated-dose toxicity studies in rats and dogs, no effects on behavioral and / or neurological parameters were observed at estimated CNS exposure levels that were similar to or lower than the expected therapeutic exposure levels.

[0517] In rats and dogs, reduced spermatogenesis was observed at exposure levels below the therapeutic level and was largely reversible within four weeks after discontinuation of administration.

[0518] Niraparib was non-mutagenic in the bacterial reverse mutagenesis assay (Ames assay), but it exhibited chromosome breakage in vitro in mammalian chromosome aberration assays and in vivo rat bone marrow micronucleus assays. This chromosome breakage effect is consistent with the genomic instability caused by niraparib's primary pharmacological activity and suggests potential genotoxicity in humans.

[0519] Reproductive and developmental toxicity studies on niraparib have not yet been conducted.

[0520] No carcinogenicity studies have been conducted on niraparib.

[0521] Abiraterone acetate In animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, organ weight loss and morphological and / or histopathological changes were observed in the reproductive organs, adrenal glands, pituitary gland, and mammary glands. All changes showed complete or partial reversibility. The changes in reproductive organs and androgen-sensitive organs were consistent with the pharmacological effects of abiraterone. All treatment-related hormonal changes reversed or showed signs of remission after a 4-week recovery period.

[0522] In fertility studies of male and female rats, abiraterone acetate reduced fertility, which was completely reversible within 4 to 16 weeks after discontinuation of abiraterone acetate.

[0523] In rat developmental toxicity studies, abiraterone acetate affected pregnancy, including reducing fetal weight and survival. Effects on the external genitalia were observed, but abiraterone acetate was not teratogenic.

[0524] In these rat fertility and developmental toxicity studies, all effects were associated with the pharmacological activity of abiraterone.

[0525] Apart from the changes in reproductive organs observed in all animal toxicology studies, non-clinical data based on routine safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenic potential studies have not revealed any specific risk to humans. Abiraterone acetate was not carcinogenic in a 6-month study in transgenic (Tg.rasH2) mice. In a 24-month rat carcinogenicity study, abiraterone acetate increased the incidence of testicular interstitial cell tumors. This finding is considered to be related to the pharmacological effects of abiraterone and is rat-specific. Abiraterone acetate was not carcinogenic in female rats.

[0526] Environmental Risk Assessment (ERA) The active substance abiraterone poses environmental risks to aquatic environments, especially fish (see Section 6.6).

[0527] 6. Medication-related matters 6.1 List of Excipients Akeega 50mg / 500mg film-coated tablets Chip Colloidal anhydrous silica Chloroprene Hydroxypropyl methylcellulose lactose monohydrate magnesium stearate microcrystalline cellulose Sodium lauryl sulfate Film coating Iron oxide black (E172) Iron oxide red (E172) Iron oxide yellow (E172) Sodium dodecyl sulfate caprylic acid glyceride Polyvinyl alcohol talc Titanium dioxide (E171) Akeega 100mg / 500mg film-coated tablets Chip Colloidal anhydrous silica Chloroprene Hydroxypropyl methylcellulose lactose monohydrate magnesium stearate microcrystalline cellulose Sodium lauryl sulfate Film coating Iron oxide red (E172) Iron oxide yellow (E172) Sodium dodecyl sulfate caprylic acid glyceride Polyvinyl alcohol talc Titanium dioxide (E171) 6.2 Incompatibilities not applicable.

[0528] 6.3 Validity period 30 months.

[0529] 6.4 Special precautions for storage This pharmaceutical product does not require any special storage conditions.

[0530] 6.5 Properties and contents of the container Each 28-day carton contains 56 film-coated sheets, packaged in two paper wallet-style packs, each containing 28 film-coated sheets, placed in a PVdC / PE / PVC blister pack with aluminum top foil.

[0531] 6.6 Special precautions for handling and other disposal Based on its mechanism of action, this drug may harm a developing fetus. Therefore, women who are pregnant or may become pregnant should handle Akeega under protective measures (e.g., wearing gloves) (see Section 4.6).

[0532] Any unused medicine or waste should be disposed of in accordance with local requirements. The medicine may pose a risk to the aquatic environment (see Section 5.3).

[0533] 7. Listing Permit Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. Listing Permit Number EU / 1 / 23 / 1722 / 001 EU / 1 / 23 / 1722 / 002 9. Date of initial market approval / Updated date 10. Date of revision of this document Detailed information about this medicine can be found on the website of the European Medicines Agency. www.ema.europa.eu.

[0534] Appendix II A. Manufacturers of bioactive substances and manufacturers with batch release responsibility B. Conditions or restrictions regarding supply and use C. Other conditions and requirements for listing approval D. Conditions or restrictions regarding the safe and effective use of drugs A. Batch Release Responsibility Manufacturer Name and address of the manufacturer responsible for batch release Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy B. Conditions or restrictions regarding supply and use The medicine must be used with a restricted medical prescription (see Appendix I: Product Characteristics Summary, Section 4.2).

[0535] C. Other conditions and requirements for listing approval • Regular Security Update Report (PSUR) For the requirements for submitting the medicine to the PSUR, please refer to the EURD List of Reference Dates (EURD List) as set out in Article 107c(7) of Directive 2001 / 83 / EC and any subsequent updates published on the European Medicines Network Portal.

[0536] The Marketing Authorization Holder (MAH) shall submit the first PSUR for this product within six months of authorization.

[0537] D. Conditions or restrictions regarding the safe and effective use of drugs • Risk Management Plan (RMP) Marketing Authorization Holders (MAHs) shall implement the required pharmacovigilance activities and interventions as detailed in the approved RMP presented in Marketing Authorization Module 1.8.2 and in any subsequent updated versions of the approved RMP.

[0538] The updated RMP should be submitted under the following circumstances: • At the request of the European Medicines Agency; • Whenever the risk management system changes, especially when new information is received that may lead to significant changes in the benefit / risk profile, or when important (pharmacovigilance or risk minimization) milestones are achieved.

[0539] • Obligation to take post-authorization measures MAH should complete the following measures within the specified time frame: Appendix III Labels and Packaging Instructions A. Tags Akeega 50mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Each film-coated tablet contains 50 mg of niraparib and 500 mg of abiraterone acetate.

[0540] It contains lactose.

[0541] For more information, please refer to the instruction manual.

[0542] 56 film-coated tablets Akeega should be taken at least two hours after a meal. Do not eat anything for at least one hour after taking Akeega.

[0543] Swallow the tablet whole. Do not break, crush, or chew the tablet.

[0544] Please read the package instructions before use.

[0545] For oral use.

[0546] Store in a place where children cannot see or reach it.

[0547] Pregnant women or women who may become pregnant should wear gloves when handling Akeega.

[0548] Validity period Please dispose of unused contents properly in accordance with local requirements.

[0549] Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium EU / 1 / 23 / 1722 / 001 batch Akeega 50mg / 500mg A two-dimensional barcode containing a unique identifier.

[0550] PC SN NN Akeega 50mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Each film-coated tablet contains 50 mg of niraparib and 500 mg of abiraterone acetate.

[0551] 28 film-coated tablets Akeega should be taken at least two hours after a meal. Do not eat anything for at least one hour after taking Akeega.

[0552] Swallow the tablet whole. Do not break, crush, or chew the tablet.

[0553] Please read the package instructions before use.

[0554] For oral use.

[0555] (1) Press and hold (see...) Figure 8 ) (2) Pull out (see Figure 9 ) Store in a place where children cannot see or reach it.

[0556] Pregnant women or women who may become pregnant should wear gloves when handling Akeega.

[0557] Validity period Please dispose of unused contents properly in accordance with local requirements.

[0558] Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium EU / 1 / 23 / 1722 / 001 batch Akeega 50mg / 500mg Akeega 50mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Janssen-Cilag International NV Validity period batch Fold to close (see) Figure 10 ) Open (see) Figure 11 ) Akeega 50mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Janssen-Cilag International NV Validity period batch Akeega 100mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Each film-coated tablet contains 100 mg of niraparib and 500 mg of abiraterone acetate.

[0559] It contains lactose.

[0560] For more information, please refer to the instruction manual.

[0561] 56 film-coated tablets Akeega should be taken at least two hours after a meal. Do not eat anything for at least one hour after taking Akeega.

[0562] Swallow the tablet whole. Do not break, crush, or chew the tablet.

[0563] Please read the package instructions before use.

[0564] For oral use.

[0565] Store in a place where children cannot see or reach it.

[0566] Pregnant women or women who may become pregnant should wear gloves when handling Akeega.

[0567] Validity period Please dispose of unused contents properly in accordance with local requirements.

[0568] Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium EU / 1 / 23 / 1722 / 002 batch Akeega 100mg / 500mg A two-dimensional barcode containing a unique identifier.

[0569] PC SN NN Akeega 100mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Each film-coated tablet contains 100 mg of niraparib and 500 mg of abiraterone acetate.

[0570] 28 film-coated tablets Akeega should be taken at least two hours after a meal. Do not eat anything for at least one hour after taking Akeega.

[0571] Swallow the tablet whole. Do not break, crush, or chew the tablet.

[0572] Please read the package instructions before use.

[0573] For oral use.

[0574] (1) Press and hold (see...) Figure 8 ) (2) Pull out (see Figure 9 ) Store in a place where children cannot see or reach it.

[0575] Pregnant women or women who may become pregnant should wear gloves when handling Akeega.

[0576] Validity period Please dispose of unused contents properly in accordance with local requirements.

[0577] Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium EU / 1 / 23 / 1722 / 002 batch Akeega 100mg / 500mg Akeega 100mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Janssen-Cilag International NV Validity period batch Fold to close (see) Figure 10 ) Open (see) Figure 11 ) Akeega 100mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Janssen-Cilag International NV Validity period batch B. Packaging Instructions Packaging Instructions: User Information Akeega 50mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Please read the entire instruction manual carefully before starting to take this medication, as it contains important information for you. .

[0578] Please keep this instruction manual. You may need to read it again.

[0579] • If you have any further questions, please consult your doctor or pharmacist.

[0580] This medication is for your personal use only. Do not transfer it to others. Even if they have the same symptoms as you, it may cause them harm.

[0581] • If you experience any side effects, tell your doctor or pharmacist. This includes any possible side effects not listed in this package insert (see Section 4).

[0582] This instruction manual contains the following content. 1. What is Akeega and what are its uses? 2. Information you need to know before taking Akeega 3. How to take Akeega 4. Possible side effects 5. How to store Akeega 6. Packaging contents and other information 1. What is Akeega and what are its uses? Akeega is a drug containing two active ingredients: niraparib and abiraterone acetate, which work in two different ways.

[0583] Akeega is used to treat adult men with prostate cancer who have specific genetic alterations, whose prostate cancer has spread to other parts of the body, and who no longer respond to medical or surgical treatments that lower testosterone (also known as metastatic castration-resistant prostate cancer).

[0584] Niraparib is a cancer drug called a PARP inhibitor. PARP inhibitors block an enzyme called poly[adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA. When PARP is blocked, cancer cells cannot repair their DNA, leading to tumor cell death and helping to control cancer.

[0585] Abiraterone blocks your body from producing testosterone; this can slow the growth of prostate cancer.

[0586] When you take this medication, your doctor will also prescribe another medication called prednisone or prednisolone. This is to reduce your risk of developing high blood pressure, excess water retention (fluid retention), or low levels of a chemical called potassium in your blood.

[0587] 2. Information you need to know before taking Akeega Do not take Akeega: • If you are allergic to niraparib or abiraterone acetate or any other ingredient in this medicine - see Section 6 for a list of ingredients.

[0588] • If you are a pregnant woman or may become pregnant.

[0589] • If you have severe liver damage.

[0590] • Used in combination with Ra-223 treatment (used to treat prostate cancer). This is because the risk of fracture or death may be increased.

[0591] If any of the above conditions apply to you, please do not take this medication. If you are unsure, please consult your doctor or pharmacist before taking this medication.

[0592] Warnings and precautions Before or during taking this medication, please inform your doctor or pharmacist if you have any of the following conditions: • Low blood cell count. Signs and symptoms you should watch for include fatigue, fever, or infection, as well as unusual bruises or bleeding. Akeega may also lower your blood cell count. Your doctor will test your blood regularly throughout your treatment.

[0593] • High blood pressure or heart failure or low potassium (low potassium can increase the risk of heart rhythm problems), a history of other heart or vascular problems, irregular or rapid heartbeat, shortness of breath, rapid weight gain, or swelling in the feet, ankles, or legs. Your doctor will measure your blood pressure regularly throughout your treatment.

[0594] • Headache, visual changes, confusion, or seizures. These may be signs of a rare neurological side effect called posterior reversible encephalopathy syndrome (PRES), which is associated with the use of niraparib, the active ingredient in Akeega.

[0595] • High fever, fatigue, and other signs and symptoms of severe infection.

[0596] • A blood clot in the lung, or one that has occurred in the past.

[0597] • Liver problems.

[0598] • Blood sugar levels that are too low or too high.

[0599] • Muscle weakness and / or muscle pain.

[0600] If any of the above applies to you (or you are unsure), please consult your doctor or pharmacist before taking this medication.

[0601] If your blood cell count remains low for an extended period while taking Akeega, this could be a sign of a more serious bone marrow problem, such as myelodysplastic syndrome or acute myeloid leukemia (AML). Your doctor may want to test your bone marrow to check for these issues.

[0602] Please discuss with your doctor or pharmacist before taking Akeega: • The effects Akeega may have on your bones.

[0603] • Take prednisone or prednisolone (another medication you must take with Akeega).

[0604] If you are unsure whether any of the above applies to you, please consult your doctor or pharmacist before taking this medication.

[0605] Blood monitoring Akeega may affect your liver, but you may not notice any symptoms of liver problems. Therefore, while you are taking this medication, your doctor will check your blood regularly to monitor for any effects on your liver.

[0606] Children and adolescents This medication is not for use in children and adolescents. If a child or adolescent accidentally swallows Akeega, take them to the hospital immediately and bring this package insert with you to the emergency room doctor.

[0607] Other drugs and Akeega If you are taking, have recently taken, or may take any other medications, tell your doctor or pharmacist. This is because Akeega may affect how some other medications work. Similarly, some other medications may affect how Akeega works.

[0608] Treatment with medications that block the body's production of testosterone may increase the risk of heart rhythm problems. Please inform your doctor if you are receiving any of the following medications: • Medications used to treat heart rhythm problems (such as quinidine, procainamide, amiodarone, and sotalol); • Medications known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and as part of drug addiction treatment; moxifloxacin, an antibiotic; antipsychotics used for severe mental illness.

[0609] If you are taking any of the medications listed above, please inform your doctor.

[0610] Akeega and food • This medication should not be taken with food (see Section 3, “Taking Akeega”), as this may increase your risk of side effects.

[0611] Pregnancy and breastfeeding Akeega is not suitable for women.

[0612] • If a pregnant woman takes this medication, it may harm her unborn child.

[0613] • Women who are pregnant or may become pregnant should wear gloves if they need to come into contact with or handle Akeega.

[0614] Male contraception using Akeega • If you have sexual intercourse with a woman who may become pregnant, use condoms and another effective method of contraception. Use contraception during treatment and for four months after stopping treatment. If you have any questions about contraception, consult your doctor.

[0615] • If you are having sex with a pregnant woman, please use a condom to protect your unborn child.

[0616] Driving and operating machinery Taking Akeega may cause weakness, difficulty concentrating, fatigue, or dizziness. This may affect your ability to drive and operate machinery. Please exercise caution when driving or operating machinery.

[0617] Akeega contains lactose and sodium. • Akeega contains lactose. If your doctor tells you you are intolerant to certain sugars, contact your doctor before taking this medication.

[0618] • Each dose of this medicine contains less than 1 mmol (23 mg) of sodium, which is essentially “sodium-free”.

[0619] 3. How to take Akeega Please always take this medication strictly as directed by your doctor. If you are unsure, please consult your doctor or pharmacist.

[0620] Dosage The recommended starting dose is 200 mg / 1,000 mg once daily.

[0621] Taking Akeega •This medicine is taken orally.

[0622] • Do not take Akeega with food.

[0623] • Akeega tablets should be taken once daily in a single dose on an empty stomach, at least one hour before or at least two hours after a meal (see Section 2, “Akeega and Food”).

[0624] Swallow the tablet whole with water. Do not break, crush, or chew the tablet. This will ensure the medication works to its fullest potential.

[0625] • Akeega is taken with a drug called prednisone or prednisolone.

[0626] ○ Strictly follow your doctor's instructions when taking prednisone or prednisolone.

[0627] ○ While you are taking Akeega, you will need to take prednisone or prednisolone daily.

[0628] ○ If you experience a medical emergency, the dosage of your prednisone or prednisolone may need to be changed. Your doctor will inform you whether you need to change the dosage of your prednisone or prednisolone. Do not stop taking prednisone or prednisolone unless advised by your doctor.

[0629] Your doctor may prescribe other medications while you are taking Akeega.

[0630] If you take an excessive amount of Akeega If you have taken too many pills, please contact your doctor. Your risk of experiencing side effects may be increased.

[0631] If you forget to take Akeega If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you remember on the same day.

[0632] If you forget to take your Akeega or prednisone or prednisolone for more than one day, please inform your doctor immediately.

[0633] Do not take double the dose to make up for a missed dose.

[0634] If you have any further questions about the use of this medication, please consult your doctor, pharmacist, or nurse.

[0635] If you stop taking Akeega Do not stop taking Akeega, prednisone, or prednisolone unless advised by your doctor.

[0636] If you have any further questions about the use of this medication, please consult your doctor, pharmacist, or nurse.

[0637] 4. Possible side effects Like all medications, this drug may cause side effects, but not everyone will experience them.

[0638] Severe side effects If you notice any of the following symptoms, stop taking Akeega immediately and seek medical attention. : Very common (potentially affecting more than one in ten people) • Bruising or bleeding that takes longer than usual after an injury - these could be signs of a low platelet count (thrombocytopenia).

[0639] • Shortness of breath, feeling extremely tired, pale skin, or a rapid heartbeat - these may be signs of low red blood cell count (anemia).

[0640] • Fever or infection – A low white blood cell count (neutropenia) may increase your risk of infection. Signs may include fever, chills, feeling weak or confused, cough, painful or burning urination. Some infections can be serious and can lead to death.

[0641] Muscle weakness, muscle twitching, or a rapid heartbeat (palpitations) may be signs of low potassium levels in your blood (hypokalemia).

[0642] • Elevated levels of alkaline phosphatase in the blood Unknown (cannot be estimated) – Not reported in the use of Akeega, but has been reported in the use of niraparib or abiraterone acetate (components of Akeega). • Allergic reactions (including potentially life-threatening severe allergic reactions). Signs include: Raised and itchy rashes (urticaria) and swelling—sometimes occurring on the face or in the mouth (i.e., angioedema)—lead to difficulty breathing, as well as collapse or loss of consciousness.

[0643] A sudden rise in blood pressure can be a medical emergency that may lead to organ damage or be life-threatening.

[0644] Other side effects If you experience any other side effects, please inform your doctor. These may include: Very common (may affect more than one in ten people): Urinary tract infection • Low white blood cell count (leukopenia), visible in blood tests. • Loss of appetite • Difficulty sleeping (insomnia) • Feeling dizzy • Shortness of breath •constipate • Feeling nauseous (nausea) •Vomit • Back pain • Joint pain • Feeling very tired • Feeling weak • Weight loss •fracture Common (potentially affecting up to one in ten people): •pneumonia • Lung infection (bronchitis) • Infections of the nose and throat (nasopharyngitis) • A type of low white blood cell count (lymphopenia), visible in blood tests. • High levels of a certain type of fat in the blood (hypertriglyceridemia) •depression • Feeling anxious •Headache • Fast heartbeat • A rapid or irregular heartbeat (palpitations) • Irregular heartbeat (atrial fibrillation) • Heart failure, leading to shortness of breath and leg swelling. • Heart disease •cough • A blood clot in the lungs can cause chest pain and shortness of breath. • Lung inflammation •stomachache •indigestion •diarrhea • Abdominal bloating • Oral ulcers Dry mouth • Liver inflammation (hepatitis), based on blood tests •rash • Muscle soreness • Blood in urine • Swelling of the hands, ankles, or feet • Elevated levels of creatinine in the blood • Elevated levels of aspartate aminotransferase in the blood • Elevated levels of alanine aminotransferase in the blood Occasional occurrence (potentially affecting up to one percent of people): • Severe infection (septicemia) that spreads from the urinary tract to the whole body. • Eye inflammation (conjunctivitis) •Feeling confused • Difficulty thinking, memorizing information, or solving problems (cognitive impairment) • Altered taste • Chest discomfort is often caused by physical activity. • Abnormal ECG (electrocardiogram) results may be a sign of heart problems. • Nosebleeds • Inflammation of the protective lining of body cavities, such as the nose, mouth, or digestive system. Sudden liver failure • Increased skin sensitivity to sunlight • Elevated levels of gamma-glutamyl transferase in the blood Unknown (cannot be estimated) – Not reported in the use of Akeega, but has been reported in the use of niraparib or abiraterone acetate (components of Akeega). • Low count of all blood cell types (pancytopenia) • Brain disorders, with symptoms including seizures (convulsions), headaches, confusion, and visual changes (posterior reversible encephalopathy syndrome or PRES), are medical emergencies that can lead to organ damage or be life-threatening.

[0645] • Adrenal gland problems (related to salt and water issues), producing too little hormone, can lead to problems such as weakness, fatigue, loss of appetite, nausea, dehydration, and skin changes. • Lung inflammation caused by an allergic reaction (allergic alveolitis) • Muscle diseases (myopathy) can lead to muscle weakness, stiffness, or spasms. • Muscle tissue breakdown (rhabdomyolysis) may cause muscle cramps or pain, fatigue, and darker urine. Report side effects If you experience any side effects, tell your doctor or pharmacist. This includes any possible side effects not listed in this package insert. You may also report side effects directly through the national reporting systems listed in Appendix V (www.ema.europa.eu / docs / en_GB / document_library / Template_or_form / 2013 / 03 / WC500139752.doc). By reporting side effects, you can help provide more information about the safety of this medication.

[0646] 5. How to store Akeega Please keep this medicine out of the sight and reach of children.

[0647] Do not use this medication after the expiry date indicated after EXP on the container (blister foil, inner wallet, outer wallet, and box). The expiry date refers to the last day of the month.

[0648] This medicine does not require any special storage conditions.

[0649] Do not dispose of any medications through wastewater or household waste. Consult your pharmacist on how to dispose of medications you no longer need. These measures will help protect the environment.

[0650] 6. Packaging contents and other information Akeega's ingredients • The active ingredients are niraparib and abiraterone acetate. Each film-coated tablet contains 50 mg of niraparib and 500 mg of abiraterone acetate.

[0651] • Other components of the core are colloidal anhydrous silica, cropovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains iron oxide black (E172), iron oxide red (E172), iron oxide yellow (E172), sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc, and titanium dioxide (E171) (see Section 2; Akeega contains lactose and sodium).

[0652] Akeega's appearance and packaging contents Akeega film-coated tablets are oval-shaped tablets ranging from yellow-orange to yellow-brown, with "N 50 A" engraved on one side and blank on the other.

[0653] Each 28-day carton contains 56 film-coated sheets, packaged in two paper wallet-style packs, each containing 28 film-coated sheets.

[0654] Listing Permit Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy For any information regarding this drug, please contact the local representative of the marketing authorization holder: Janssen-Cilag NV, Belgium. Phone: +32 14 64 94 11 janssen@jacbe.jnj.com Lithuanian UAB "JOHNSON & JOHNSON" Phone: +3705 278 68 88 lt@its.jnj.com Bulgaria "Джонсън & Джонсън България" ЕООД Tel: +359 2 489 94 00jjsafety@its.jnj.com Janssen-Cilag NV, Luxembourg. Tel: +32 14 6494 11 janssen@jacbe.jnj.com Janssen-Cilag sro, Czech Republic. Telephone: +420 227012 227 Magyarország Janssen-Cilag Kft. Tel: +361 884 2858 janssenhu@its.jnj.com Janssen-Cilag A / S, Denmark. Tel: +45 4594 8282 jacdk@its.jnj.com AM MANGION LTD, Malta Tel: +356 23976000 Janssen-Cilag GmbH, Germany. Tel: +49 2137 955955 jancil@its.jnj.com Janssen-Cilag BV, Netherlands. Phone: +31 76711 1111 janssen@jacnl.jnj.com Estonian UAB "JOHNSON & JOHNSON" Eesti filiaal phone: +372 617 7410 ee@its.jnj.com Janssen-Cilag AS, Norway. Phone: +47 24 1265 00. jacno@its.jnj.com Janssen-Cilag Greece Φαρμακευτική Α.Ε.Β.Ε. Phone: +30 210 80 90 000 Janssen-Cilag Pharma GmbH, Austria. Tel: +43 1 610 300 Janssen-Cilag, SA, Spain. Phone: +34 91 722 8100 contacto@its.jnj.com Janssen-Cilag Polska Sp. z oo, Poland Telephone: +48 22 237 60 00 Janssen-Cilag, France. Telephone: 0 800 25 50 75 / +33 1 55 00 40 03 medisource@its.jnj.com Janssen-Cilag Farmacêutica, Lda., Portugal. Tel: +351 214 368 600 Johnson & Johnson SE doo, Croatia. Phone: +385 1 6610 700. jjsafety@JNJCR.JNJ.com Johnson & Johnson România SRL, Romania: +40 21 207 1800 Janssen Sciences Ireland UC Phone: 1 800709 122 medinfo@its.jnj.com Johnson & Johnson doo, Slovenia. Phone: +386 1 401 18 00. Janssen_safety_slo@its.jnj.com Janssen-Cilag AB, Iceland. Contact via Vistar: +354 535 7000 janssen@vistor.is Johnson & Johnson, Slovakia Telephone: +421 232 408 400 Janssen-Cilag SpA, Italy. Phone: 800.688.777 / +39 02 2510 1 janssenita@its.jnj.com Janssen-Cilag Oy, Finland. Phone: +358 207531 300. jacfi@its.jnj.com Cyprus Βαρνάβας Χατζηπαναγής Λτδ Tel: +357 22 207 700 Janssen-Cilag AB, Sweden. Phone: +46 8 62650 00. jacse@its.jnj.com Latvia UAB "JOHNSON & JOHNSON" filiāle Latvijā Phone: +371 678 93561 lv@its.jnj.com United Kingdom (Northern Ireland) Janssen Sciences IrelandUC Tel: +44 1 494 567 444 medinfo@its.jnj.com This instruction manual was last revised in YYYY / MM.

[0655] Other information sources Detailed information about this medicine can be found on the website of the European Medicines Agency: www.ema.europa.eu Packaging Instructions: User Information Akeega 100mg / 500mg film-coated tablets Niraparib / Abiraterone Acetate Please read the entire instruction manual carefully before starting to take this medication, as it contains important information for you. .

[0656] Please keep this instruction manual. You may need to read it again.

[0657] • If you have any further questions, please consult your doctor or pharmacist.

[0658] This medication is for your personal use only. Do not transfer it to others. Even if they have the same symptoms as you, it may cause them harm.

[0659] • If you experience any side effects, tell your doctor or pharmacist. This includes any possible side effects not listed in this package insert (see Section 4).

[0660] This instruction manual contains the following content. 1. What is Akeega and what are its uses? 2. Information you need to know before taking Akeega 3. How to take Akeega 4. Possible side effects 5. How to store Akeega 6. Packaging contents and other information 1. What is Akeega and what are its uses? Akeega is a drug containing two active ingredients: niraparib and abiraterone acetate, which work in two different ways.

[0661] Akeega is used to treat adult men with prostate cancer who have specific genetic alterations, whose prostate cancer has spread to other parts of the body, and who no longer respond to medical or surgical treatments that lower testosterone (also known as metastatic castration-resistant prostate cancer).

[0662] Niraparib is a cancer drug called a PARP inhibitor. PARP inhibitors block an enzyme called poly[adenosine diphosphate-ribose] polymerase (PARP). PARP helps cells repair damaged DNA. When PARP is blocked, cancer cells cannot repair their DNA, leading to tumor cell death and helping to control cancer.

[0663] Abiraterone blocks your body from producing testosterone; this can slow the growth of prostate cancer.

[0664] When you take this medication, your doctor will also prescribe another medication called prednisone or prednisolone. This is to reduce your risk of developing high blood pressure, excess water retention (fluid retention), or low levels of a chemical called potassium in your blood.

[0665] 2. Information you need to know before taking Akeega Do not take Akeega: • If you are allergic to niraparib or abiraterone acetate or any other ingredient in this medicine - see Section 6 for a list of ingredients.

[0666] • If you are a pregnant woman or may become pregnant.

[0667] • If you have severe liver damage.

[0668] • Used in combination with Ra-223 treatment (used to treat prostate cancer). This is because the risk of fracture or death may be increased.

[0669] If any of the above conditions apply to you, please do not take this medication. If you are unsure, please consult your doctor or pharmacist before taking this medication.

[0670] Warnings and precautions Before or during taking this medication, please inform your doctor or pharmacist if you have any of the following conditions: • Low blood cell count. Signs and symptoms you should watch for include fatigue, fever, or infection, as well as unusual bruises or bleeding. Akeega may also lower your blood cell count. Your doctor will test your blood regularly throughout your treatment.

[0671] • High blood pressure or heart failure or low potassium (low potassium can increase the risk of heart rhythm problems), a history of other heart or vascular problems, irregular or rapid heartbeat, shortness of breath, rapid weight gain, or swelling in the feet, ankles, or legs. Your doctor will measure your blood pressure regularly throughout your treatment.

[0672] • Headache, visual changes, confusion, or seizures. These may be signs of a rare neurological side effect called posterior reversible encephalopathy syndrome (PRES), which is associated with the use of niraparib, the active ingredient in Akeega.

[0673] • High fever, fatigue, and other signs and symptoms of severe infection.

[0674] • A blood clot in the lung, or one that has occurred in the past.

[0675] • Liver problems.

[0676] • Blood sugar levels that are too low or too high.

[0677] • Muscle weakness and / or muscle pain.

[0678] If any of the above applies to you (or you are unsure), please consult your doctor or pharmacist before taking this medication.

[0679] If your blood cell count remains low for an extended period while taking Akeega, this could be a sign of a more serious bone marrow problem, such as myelodysplastic syndrome or acute myeloid leukemia (AML). Your doctor may want to test your bone marrow to check for these issues.

[0680] Please discuss with your doctor or pharmacist before taking Akeega: • The effects Akeega may have on your bones.

[0681] • Take prednisone or prednisolone (another medication you must take with Akeega).

[0682] If you are unsure whether any of the above applies to you, please consult your doctor or pharmacist before taking this medication.

[0683] Blood monitoring Akeega may affect your liver, but you may not notice any symptoms of liver problems. Therefore, while you are taking this medication, your doctor will check your blood regularly to monitor for any effects on your liver.

[0684] Children and adolescents This medication is not for use in children and adolescents. If a child or adolescent accidentally swallows Akeega, take them to the hospital immediately and bring this package insert with you to the emergency room doctor.

[0685] Other drugs and Akeega If you are taking, have recently taken, or may take any other medications, tell your doctor or pharmacist. This is because Akeega may affect how some other medications work. Similarly, some other medications may affect how Akeega works.

[0686] Treatment with medications that block the body's production of testosterone may increase the risk of heart rhythm problems. Please inform your doctor if you are receiving any of the following medications: • Medications used to treat heart rhythm problems (such as quinidine, procainamide, amiodarone, and sotalol); • Medications known to increase the risk of heart rhythm problems (e.g., methadone), used for pain relief and as part of drug addiction treatment; moxifloxacin, an antibiotic; antipsychotics used for severe mental illness.

[0687] If you are taking any of the medications listed above, please inform your doctor.

[0688] Akeega and food • This medication should not be taken with food (see Section 3, “Taking Akeega”), as this may increase your risk of side effects.

[0689] Pregnancy and breastfeeding Akeega is not suitable for women.

[0690] • If a pregnant woman takes this medication, it may harm her unborn child.

[0691] • Women who are pregnant or may become pregnant should wear gloves if they need to come into contact with or handle Akeega.

[0692] Male contraception using Akeega • If you have sexual intercourse with a woman who may become pregnant, use condoms and another effective method of contraception. Use contraception during treatment and for four months after stopping treatment. If you have any questions about contraception, consult your doctor.

[0693] • If you are having sex with a pregnant woman, please use a condom to protect your unborn child.

[0694] Driving and operating machinery Taking Akeega may cause weakness, difficulty concentrating, fatigue, or dizziness. This may affect your ability to drive and operate machinery. Please exercise caution when driving or operating machinery.

[0695] Akeega contains lactose and sodium. • Akeega contains lactose. If your doctor tells you you are intolerant to certain sugars, contact your doctor before taking this medication.

[0696] • Each dose of this medicine contains less than 1 mmol (23 mg) of sodium, which is essentially “sodium-free”.

[0697] 3. How to take Akeega Please always take this medication strictly as directed by your doctor. If you are unsure, please consult your doctor or pharmacist.

[0698] Dosage The recommended starting dose is 200 mg / 1,000 mg (two tablets) once daily.

[0699] Taking Akeega •This medicine is taken orally.

[0700] • Do not take Akeega with food.

[0701] • Akeega tablets should be taken once daily in a single dose on an empty stomach, at least one hour before or at least two hours after a meal (see Section 2, “Akeega and Food”).

[0702] Swallow the tablet whole with water. Do not break, crush, or chew the tablet. This will ensure the medication works to its fullest potential.

[0703] • Akeega is taken with a drug called prednisone or prednisolone.

[0704] ○ Strictly follow your doctor's instructions when taking prednisone or prednisolone.

[0705] ○ While you are taking Akeega, you will need to take prednisone or prednisolone daily.

[0706] ○ If you experience a medical emergency, the dosage of your prednisone or prednisolone may need to be changed. Your doctor will inform you whether you need to change the dosage of your prednisone or prednisolone. Do not stop taking prednisone or prednisolone unless advised by your doctor.

[0707] Your doctor may prescribe other medications while you are taking Akeega.

[0708] If you take an excessive amount of Akeega If you have taken too many pills, please contact your doctor. Your risk of experiencing side effects may be increased.

[0709] If you forget to take Akeega If you forget to take Akeega or prednisone or prednisolone, take your usual dose as soon as you remember on the same day.

[0710] If you forget to take your Akeega or prednisone or prednisolone for more than one day, please inform your doctor immediately.

[0711] Do not take double the dose to make up for a missed dose.

[0712] If you have any further questions about the use of this medication, please consult your doctor, pharmacist, or nurse.

[0713] If you stop taking Akeega Do not stop taking Akeega, prednisone, or prednisolone unless advised by your doctor.

[0714] If you have any further questions about the use of this medication, please consult your doctor, pharmacist, or nurse.

[0715] 4. Possible side effects Like all medications, this drug may cause side effects, but not everyone will experience them.

[0716] Severe side effects If you notice any of the following symptoms, stop taking Akeega immediately and seek medical attention: Very common (potentially affecting more than one in ten people) • Bruising or bleeding that takes longer than usual after an injury - these could be signs of a low platelet count (thrombocytopenia).

[0717] • Shortness of breath, feeling extremely tired, pale skin, or a rapid heartbeat - these may be signs of low red blood cell count (anemia).

[0718] • Fever or infection – A low white blood cell count (neutropenia) may increase your risk of infection. Signs may include fever, chills, feeling weak or confused, cough, painful or burning urination. Some infections can be serious and can lead to death.

[0719] Muscle weakness, muscle twitching, or a rapid heartbeat (palpitations) may be signs of low potassium levels in your blood (hypokalemia).

[0720] • Elevated levels of alkaline phosphatase in the blood Unknown (cannot be estimated) – Not reported in the use of Akeega, but has been reported in the use of niraparib or abiraterone acetate (components of Akeega). • Allergic reactions (including potentially life-threatening severe allergic reactions). Signs include: raised and itchy rash (urticaria) and swelling—sometimes occurring on the face or in the mouth (i.e., angioedema), leading to difficulty breathing, as well as collapse or loss of consciousness.

[0721] A sudden rise in blood pressure can be a medical emergency that may lead to organ damage or be life-threatening.

[0722] Other side effects If you experience any other side effects, please inform your doctor. These may include: Very common (may affect more than one in ten people): Urinary tract infection • Low white blood cell count (leukopenia), visible in blood tests. • Loss of appetite • Difficulty sleeping (insomnia) • Feeling dizzy • Shortness of breath •constipate • Feeling nauseous (nausea) •Vomit • Back pain • Joint pain • Feeling very tired • Feeling weak • Weight loss •fracture Common (potentially affecting up to one in ten people): •pneumonia • Lung infection (bronchitis) • Infections of the nose and throat (nasopharyngitis) • A type of low white blood cell count (lymphopenia), visible in blood tests. • High levels of a certain type of fat in the blood (hypertriglyceridemia) •depression • Feeling anxious •Headache • Fast heartbeat • A rapid or irregular heartbeat (palpitations) • Irregular heartbeat (atrial fibrillation) • Heart failure, leading to shortness of breath and leg swelling. • Heart disease •cough • A blood clot in the lungs can cause chest pain and shortness of breath. • Lung inflammation •stomachache •indigestion •diarrhea • Abdominal bloating • Oral ulcers Dry mouth • Liver inflammation (hepatitis), based on blood tests •rash • Muscle soreness • Blood in urine • Swelling of the hands, ankles, or feet • Elevated levels of creatinine in the blood • Elevated levels of aspartate aminotransferase in the blood • Elevated levels of alanine aminotransferase in the blood Occasional occurrence (potentially affecting up to one percent of people): • Severe infection (septicemia) that spreads from the urinary tract to the whole body. • Eye inflammation (conjunctivitis) •Feeling confused • Difficulty thinking, memorizing information, or solving problems (cognitive impairment) • Altered taste • Chest discomfort is often caused by physical activity. • Abnormal ECG (electrocardiogram) results may be a sign of heart problems. • Nosebleeds • Inflammation of the protective lining of body cavities, such as the nose, mouth, or digestive system. Sudden liver failure • Increased skin sensitivity to sunlight • Elevated levels of gamma-glutamyl transferase in the blood Unknown (cannot be estimated) – Not reported in use with Akeega, but in niraparib or abiraterone acetate. There are reports regarding the use of (Akeega's components). • Low count of all blood cell types (pancytopenia) • Brain disorders, with symptoms including seizures (convulsions), headaches, confusion, and visual changes (posterior reversible encephalopathy syndrome or PRES), are medical emergencies that can lead to organ damage or be life-threatening.

[0723] • Adrenal gland problems (related to salt and water issues), producing too little hormone, can lead to problems such as weakness, fatigue, loss of appetite, nausea, dehydration, and skin changes. • Lung inflammation caused by an allergic reaction (allergic alveolitis) • Muscle diseases (myopathy) can lead to muscle weakness, stiffness, or spasms. • Muscle tissue breakdown (rhabdomyolysis) may cause muscle cramps or pain, fatigue, and darker urine. Report side effects If you experience any side effects, tell your doctor or pharmacist. This includes any possible side effects not listed in this package insert. You can also report side effects directly through the national reporting systems listed at www.ema.europa.eu / docs / en_GB / document_library / Template_or_form / 2013 / 03 / WC500139752.doc. By reporting side effects, you can help provide more information about the safety of this medication.

[0724] 5. How to store Akeega Please keep this medicine out of the sight and reach of children.

[0725] Do not use this medication after the expiry date indicated after EXP on the container (blister foil, inner wallet, outer wallet, and box). The expiry date refers to the last day of the month.

[0726] This medicine does not require any special storage conditions.

[0727] Do not dispose of any medications through wastewater or household waste. Consult your pharmacist on how to dispose of medications you no longer need. These measures will help protect the environment.

[0728] 6. Packaging contents and other information Akeega's ingredients • The active ingredients are niraparib and abiraterone acetate. Each film-coated tablet contains 100 mg of niraparib and 500 mg of abiraterone acetate.

[0729] • Other components of the tablet core are colloidal anhydrous silica, cropovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains iron oxide red (E172), iron oxide yellow (E172), sodium lauryl sulfate, glyceryl monocaprylate, polyvinyl alcohol, talc, and titanium dioxide (E171) (see Section 2; Akeega contains lactose and sodium). Akeega's appearance and packaging contents Akeega film-coated tablets are orange oval tablets with "N 100 A" engraved on one side and blank on the other.

[0730] Each 28-day carton contains 56 film-coated sheets, packaged in two paper wallet-style packs, each containing 28 film-coated sheets.

[0731] Listing Permit Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Cilag SpA Via C. Janssen, Borgo San Michele Latina 04100 Italy For any information regarding this drug, please contact the local representative of the marketing authorization holder: Janssen-Cilag NV, Belgium. Phone: +32 14 64 94 11 janssen@jacbe.jnj.com Lithuanian UAB "JOHNSON & JOHNSON" Phone: +3705 278 68 88 lt@its.jnj.com Bulgaria "Джонсън & Джонсън България" ЕООД Tel: +359 2 489 94 00jjsafety@its.jnj.com Janssen-Cilag NV, Luxembourg. Tel: +32 14 6494 11 janssen@jacbe.jnj.com Janssen-Cilag sro, Czech Republic. Telephone: +420 227012 227 Magyarország Janssen-Cilag Kft. Tel: +361 884 2858 janssenhu@its.jnj.com Janssen-Cilag A / S, Denmark. Tel: +45 4594 8282 jacdk@its.jnj.com AM MANGION LTD, Malta Tel: +356 23976000 Janssen-Cilag GmbH, Germany. Tel: +49 2137 955955 jancil@its.jnj.com Janssen-Cilag BV, Netherlands. Phone: +31 76711 1111 janssen@jacnl.jnj.com Estonian UAB "JOHNSON & JOHNSON" Eesti filiaal phone: +372 617 7410 ee@its.jnj.com Janssen-Cilag AS, Norway. Phone: +47 24 1265 00. jacno@its.jnj.com Janssen-Cilag Greece Φαρμακευτική Α.Ε.Β.Ε. Phone: +30 210 80 90 000 Janssen-Cilag Pharma GmbH, Austria. Tel: +43 1 610 300 Janssen-Cilag, SA, Spain. Phone: +34 91 722 8100 contacto@its.jnj.com Janssen-Cilag Polska Sp. z oo, Poland Telephone: +48 22 237 60 00 Janssen-Cilag, France. Telephone: 0 800 25 50 75 / +33 1 55 00 40 03 medisource@its.jnj.com Janssen-Cilag Farmacêutica, Lda., Portugal. Tel: +351 214 368 600 Johnson & Johnson SE doo, Croatia. Phone: +385 1 6610 700. jjsafety@JNJCR.JNJ.com Johnson & Johnson România SRL, Romania: +40 21 207 1800 Janssen Sciences Ireland UC Phone: 1 800709 122 medinfo@its.jnj.com Johnson & Johnson doo, Slovenia. Phone: +386 1 401 18 00. Janssen_safety_slo@its.jnj.com Janssen-Cilag AB, Iceland. Contact via Vistar: +354 535 7000 janssen@vistor.is Johnson & Johnson, Slovakia Telephone: +421 232 408 400 Janssen-Cilag SpA, Italy. Phone: 800.688.777 / +39 02 2510 1 janssenita@its.jnj.com Janssen-Cilag Oy, Finland. Phone: +358 207531 300. jacfi@its.jnj.com Cyprus Βαρνάβας Χατζηπαναγής Λτδ Tel: +357 22 207 700 Janssen-Cilag AB, Sweden. Phone: +46 8 62650 00. jacse@its.jnj.com Latvia UAB "JOHNSON & JOHNSON" filiāle Latvijā Phone: +371 678 93561 lv@its.jnj.com United Kingdom (Northern Ireland) Janssen Sciences IrelandUC Tel: +44 1 494 567 444 medinfo@its.jnj.com This instruction manual was last revised in YYYY / MM.

[0732] Other information sources Detailed information about this medicine can be found on the website of the European Medicines Agency: www.ema.europa.eu Example 3 – Drug product label approved by Health Canada; Approval date: June 23, 2023 Product Special Commentary Including patient medication information Pr AKEEGA™ Niraparib and Abiraterone Acetate Tablets 100mg niraparib (in the form of niraparib tosylate) / 500mg abiraterone acetate, 50mg niraparib (in the form of niraparib tosylate) / 500mg abiraterone acetate Oral administration Antitumor drugs / androgen biosynthesis inhibitors Janssen Inc. Toronto, Ontario M3C 1L9 Initial license date: June 7, 2023 Submission control number: 265223 Table of contents Chapters or sub-chaps that are not applicable during authorization are not listed. Table of Contents 2 Part I: Information on Healthcare Professionals 4 1. Indications 4 1.1 Pediatrics (<18 years old) 4 1.2 Elderly patients (≥65 years old) 4 2. Contraindications 4 3. Important Warnings and Precautions Box 4 4. Dosage and administration 5. 4.1 Dosage considerations 5 4.2 Recommended Dosage and Dosage Adjustment 5 4.3 Reconstitute 7 4.4 Administration 8 4.5 Missed dose 8 5. Overdose 8. 6. Dosage form, strength, ingredients and packaging 8 7 Warnings and Precautions 9 7.1 Special populations 14 7.1.1 Pregnant women 14 7.1.3 Pediatrics (<18 years old) 14 7.1.4 Elderly patients (≥65 years old) 14 8 Adverse Reactions 14 8.1 Overview of Adverse Reactions 14 8.2 Adverse Reactions in Clinical Trials 15 8.3 Less common adverse reactions in clinical trials 18 8.4 Abnormal laboratory test results: hematological, clinical chemistry and other quantitative data 19 8.5 Post-marketing adverse reactions 19 9. Drug Interactions 20 9.2 Overview of Drug Interactions 20 9.3 Drug-behavioral interactions 21 9.4 Drug-Drug Interactions 21 9.5 Drug-Food Interactions 23 9.6 Drug-Herbal Interactions 23 9.7 Drug-Laboratory Testing Interactions 23 10 Clinical Pharmacology 23 10.1 Mechanism of Action 23 10.2 Pharmacodynamics 24 10.3 Pharmacokinetics 26 11 Storage, stability and disposal 28 12 Special Handling Instructions 28 Part II: Scientific Information 29 13 Drug Information 29 14 Clinical trials 30 14.1 Clinical trials classified by indication 30 15 Microbiology 36 16 Non-clinical toxicology 36 Patient medication information 39 Part I: Information for Healthcare Professionals Indications Pr AKEEGA ™ (Niraparib and Abiraterone acetate) are indicated in combination with prednisone or prednisolone for: Treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) harboring harmful or suspected harmful BRCA mutations (germline and / or somatic mutations) who are asymptomatic or have mild symptoms and for whom chemotherapy is not clinically indicated. Initiation of AKEEGA ™ Before treatment, it is essential to confirm that the patient has a BRCA mutation.

[0733] Conditional marketing authorization based on imaging progression-free survival, time to symptom progression, and time to cytotoxic chemotherapy (see 14 Clinical Trials). Continued approval for this indication may be contingent upon validation and description of clinical benefit in subsequent analyses.

[0734] AKEEGA ™ The efficacy in patients with visceral metastases is uncertain (see 14 clinical trials). Pediatrics (<18 years old) Health Canada has no available data; therefore, Health Canada has not approved the pediatric indication. Elderly patients (≥65 years old) No overall difference in safety and efficacy of the combination therapy of niraparib and abiraterone acetate was observed between these patients and younger patients, but the possibility that some older individuals may be more sensitive cannot be ruled out (see 7 Warnings and Precautions).

[0735] Contraindications AKEEGA ™ Disabled for: • Patients with hypersensitivity to any component or container part of this drug or formulation. See 6 Dosage Forms, Strengths, Ingredients, and Packaging for a complete list.

[0736] Serious warnings and precautions box Dosage and administration Dosage considerations AKEEGA ™ It is a fixed-dose combination of niraparib and abiraterone acetate. (At the start of AKEEGA) ™ Prior to treatment, the presence of a BRCA mutation was confirmed using a validated test (see 14 Clinical Trials).

[0737] Recommended dosage and dosage adjustment AKEEGA ™ The recommended dose is 200 mg niraparib and 1,000 mg abiraterone acetate (two 100 mg / 500 mg tablets) once daily, which must be taken on an empty stomach at approximately the same time each day (see 4 Dosage and Administration, Dosage). For dose reduction to 100 mg niraparib and 1,000 mg abiraterone acetate, low-strength tablets (two 50 mg / 500 mg tablets) are recommended (see 4 Dosage and Administration, Dosage Modification). If further reduction of the niraparib dose to below 100 mg / day is required, AKEEGA should be discontinued.

[0738] Dosage of prednisone or prednisolone AKEEGA ™ Use daily with 10 mg prednisone or prednisolone.

[0739] Stop treatment Treatment should continue until disease progression, clear clinical progression, or unacceptable toxicity occurs.

[0740] Dosage modification Hematological adverse reactions Dosage adjustment recommendations for anemia, thrombocytopenia, and neutropenia are listed in Tables 1 and 2.

[0741] Table 1: Dosage Adjustment Recommendations for Anemia 1 in AKEEGA ™ During treatment interruptions, physicians may consider administering abiraterone acetate and prednisone to maintain the daily dose of abiraterone acetate (see the abiraterone acetate product monograph).

[0742] Table 2: Dosage Adjustment Recommendations for Thrombocytopenia and Neutropenia 1 In AKEEGA related to hematologic toxicity ™ During treatment interruptions, physicians should generally continue using abiraterone acetate plus prednisone or prednisolone (see the abiraterone acetate product treatise). 2 If a patient requires platelet transfusion, or experiences neutropenic fever or neutropenia requiring granulocyte colony-stimulating factor, and is considered to have grade ≥3 AE and AKEEGA ™ If toxicity is involved, the study drug is discontinued and restarted at a reduced dose level after grade 1 remission or baseline. If AKEEGA ™ If the dosage was previously reduced due to the same hematologic toxicity, then AKEEGA should be discontinued. ™ Non-hematological adverse reactions For drug-related grade ≥3 toxicities, if the toxicity cannot be clearly attributed to niraparib alone or abiraterone acetate alone, AKEEGA should be discontinued. ™ AKEEGA should not be restarted until toxic symptoms have resolved to Grade 1 or baseline. ™ Treatment. To resume treatment, begin with monotherapy with AAP. If toxicity persists to baseline / grade 1, switch to AKEEGA at least 7 days after restarting AAP. ™ treat.

[0743] If the patient is taking a reduced dose of AKEEGA ™ (100mg / 1,000mg) If grade 3 or higher treatment-related adverse reactions persist for more than 28 days, AKEEGA must be discontinued. ™ .

[0744] For treatment-related hypertensive crisis, permanent discontinuation of AKEEGA is recommended. ™ .

[0745] Hepatotoxicity For patients experiencing grade 3 or higher hepatotoxicity (elevated alanine aminotransferase [ALT] or aspartate aminotransferase [AST] exceeding five times the upper limit of normal [ULN]), AKEEGA should be discontinued. ™ Treatment and close monitoring of liver function are necessary. Only after liver function tests return to the patient's baseline levels can a reduced dose level (one standard strength AKEEGA tablet) be administered. ™ Treatment should be restarted with tablets (equivalent to 100 mg niraparib and 500 mg abiraterone acetate). For patients restarting treatment, serum transaminases should be monitored at least every two weeks for the first three months, and monthly thereafter. If hepatotoxicity recurs at a reduced dose of 100 mg / 500 mg (1 tablet) daily, AKEEGA should be discontinued. ™ treat.

[0746] For patients experiencing severe hepatotoxicity (ALT or AST 20 times higher than ULN), AKEEGA should be permanently discontinued. ™ For patients with concurrent elevations of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN, and without biliary obstruction or other causes of such elevations, AKEEGA should be permanently discontinued. ™ (See 7 Warnings and Precautions) Recommended monitoring About AKEEGA ™ For monitoring required before and during treatment, see 7 Warnings and Precautions.

[0747] Special populations Pediatrics (<18 years old): Health Canada has not approved this indication for pediatric use.

[0748] Elderly patients (≥65 years old) No dose adjustment is required for elderly patients (see 10.3 Pharmacokinetics).

[0749] Liver function impairment No dose adjustment is required for patients with mild hepatic impairment (AST or ALT ≤ 3 × ULN or serum total bilirubin ≤ 1.5 × ULN). AKEEGA should not be used in patients with moderate to severe hepatic impairment. ™ (See box 3 for serious warnings and precautions; 10.3 for pharmacokinetics).

[0750] Kidney damage No dose adjustment is required for patients with mild to moderate renal impairment (see 10.3 Pharmacokinetics). AKEEGA has not been studied in patients with severe renal impairment (creatinine clearance <30 mL / min). ™ .

[0751] Reconstitute not applicable application AKEEGA ™ Must be taken on an empty stomach. AKEEGA ™ It must be taken at least two hours after a meal, and when taking AKEEGA ™ Do not eat for at least one hour after taking the tablet. The tablet must be swallowed whole with water (see 10.3 Pharmacokinetics – Absorption). Do not break, crush, or chew the tablet.

[0752] In AKEEGA ™ Treatment requires the use of gonadotropin-releasing hormone (GnRH) agonists, or the patient must have previously undergone orchiectomy.

[0753] Missed dose If you miss a dose of AKEEGA ™ For missed doses of prednisone or prednisolone, the regular daily dose and schedule should be resumed the following day. Do not take additional tablets to make up for missed doses.

[0754] Overdose AKEEGA occurred ™ There is no specific treatment for medication overdose. In the event of an overdose, the physician should take general supportive measures and treat the patient symptomatically.

[0755] Dosage form, strength, ingredients and packaging Dosage form, strength, ingredients and packaging AKEEGA ™ The tablets are available in regular strength (100 mg niraparib (in the form of niraparib tosylate) and 500 mg abiraterone acetate) and low strength (50 mg niraparib (in the form of niraparib tosylate) and 500 mg abiraterone acetate): AKEEGA ™ 100mg niraparib (in the form of niraparib tosylate) and 500mg abiraterone acetate tablets: orange, oval, tablets (22mm × 11mm), with "N 100 A" engraved on one side and blank on the other.

[0756] AKEEGA ™ 50mg niraparib (in the form of niraparib tosylate) and 500mg abiraterone acetate tablets: yellow-orange to yellow-brown, oval tablets (22mm × 11mm), with "N 50 A" engraved on one side and blank on the other side.

[0757] Two strengths of AKEEGA ™ The tablets will be supplied in 150ml high-density polyethylene (HDPE) bottles, with 60 tablets per bottle.

[0758] Warnings and precautions Please refer to box 3 for critical warnings and precautions.

[0759] General AKEEGA ™ Use daily with 10 mg prednisone or prednisolone. (AKEEGA) ™ Treatment requires the use of gonadotropin-releasing hormone (GnRH) agonists, or the patient must have previously undergone orchiectomy.

[0760] AKEEGA ™ Must be taken on an empty stomach. AKEEGA ™ It must be taken at least two hours after a meal, and when taking AKEEGA ™ Do not eat for at least one hour afterward. Tablets must be swallowed whole with water (see 4 Dosage and Administration, and 10.3 Pharmacokinetics - Absorption). Lactose intolerance This medication contains lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

[0761] Carcinogenicity and Mutagenicity Myelodysplastic syndrome / acute myeloid leukemia (MDS / AML) In trials of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, there have been reports of MDS / AML (including fatal outcomes) in patients receiving niraparib monotherapy (see ZEJULA). ® Product Monograph).

[0762] In cohort 1 of the MAGNITUDE study (see 8 Adverse Events), the median follow-up duration was 26.8 months in the niraparib + AAP group and 26.9 months in the placebo + AAP group. No AML cases were reported in the niraparib + AAP group, while one subject (0.5%) reported AML in the placebo + AAP group.

[0763] For suspected MDS / AML or long-term hematologic toxicities that do not improve with treatment interruption or dose reduction, patients should be referred to a hematologist for further evaluation. If MDS and / or AML is confirmed, AKEEGA should be permanently discontinued. ™ treat.

[0764] cardiovascular Patients with a history of cardiovascular disease should use AKEEGA with caution. ™ Heart failure should be treated and cardiac function optimized before and during treatment in patients at significant risk of congestive heart failure (e.g., a history of heart failure or cardiac events such as ischemic heart disease). Symptoms of congestive heart failure should be monitored every two weeks for the first three months, and monthly thereafter. AKEEGA ™ Safety in patients with clinically significant heart disease (evidence including myocardial infarction, arterial and venous thrombotic events within the past six months, severe or unstable angina, or NYHA class II to IV heart failure or cardiac ejection fraction <50%) is unclear because these patients were excluded from the MAGNITUDE study.

[0765] hypertension AKEEGA ™ It may cause high blood pressure. Pre-existing high blood pressure may lead to AKEEGA. ™ It should be adequately controlled before treatment. (Using AKEEGA) ™ During treatment, blood pressure should be monitored weekly for at least the first two months, then monthly for the first year, and then every other month thereafter.

[0766] Hypokalemia, fluid retention AKEEGA ™ Hypokalemia and fluid retention may occur due to elevated mineralocorticoid levels caused by CYP17 inhibition (see 8 Adverse Reactions) (see 10.2 Pharmacodynamics). Concomitant use of corticosteroids to inhibit adrenocorticotropic hormone (ACTH) drive may reduce the incidence and severity of these adverse reactions. Caution should be exercised when treating patients with underlying health conditions that may be exacerbated by hypokalemia. In cases of AKEEGA... ™ QT interval prolongation has been observed in patients with treatment-associated hypokalemia. Hypokalemia and fluid retention should be corrected and controlled.

[0767] Fluid retention (weight gain, peripheral edema) should be monitored every two weeks for the first three months, and then monthly thereafter, with any abnormalities corrected.

[0768] Venous thromboembolic events Using AKEEGA ™ Venous thromboembolic events (VTE), including pulmonary embolism, have occurred in patients treated (see 8 Adverse Reactions). Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism, and provide appropriate medical treatment.

[0769] Driving and operating machinery Taking AKEEGA ™ Patients may experience weakness, fatigue, and dizziness. AKEEGA ™ It may affect the ability to drive or operate machinery. Patients should exercise caution when driving or operating vehicles or potentially hazardous machinery.

[0770] Endocrine and Metabolic hypoglycemia There have been reports of hypoglycemia occurring when abiraterone acetate plus prednisone or prednisolone is administered to patients with pre-existing diabetes who are receiving pioglitazone or repaglinide (see 9 Drug Interactions); therefore, blood glucose levels should be monitored in patients with diabetes.

[0771] hematology Hematological adverse reactions Hematological adverse reactions (anemia, neutropenia, and thrombocytopenia) have been reported in patients treated with niraparib monotherapy and in combination therapy (see 8 Adverse Reactions).

[0772] In the MAGNITUDE study, among patients in cohort 1 who received niraparib plus AAP, the overall incidence of grade 3 anemia, neutropenia, and thrombocytopenia was 29.7%, 6.6%, and 6.6%, respectively.

[0773] It is recommended to test complete blood cell counts weekly during the first month, bi-weekly for the next two months, monthly for the first year thereafter, and then monthly for the remainder of treatment (see 4 Dosage and Administration).

[0774] Based on individual laboratory values, weekly monitoring may be necessary during the second month. AKEEGA should be discontinued if the patient develops severe, persistent hematologic toxicity (including pancytopenia) that does not improve within 28 days of treatment interruption. ™ Due to the risk of thrombocytopenia, AKEEGA should be taken... ™ Patients with this condition should use other medications known to reduce platelet count with caution.

[0775] Liver / Gallbladder / Pancreas Liver function impairment There is no information about AKEEGA yet. ™ Data on the clinical safety and efficacy of AKEEGA in patients with moderate or severe hepatic impairment (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤3×ULN, or Child-Pugh class B or C). AKEEGA should not be used in patients with moderate to severe hepatic impairment. ™ (See box 3 for serious warnings and precautions, box 4 for dosage and administration, and box 10.3 for pharmacokinetic properties).

[0776] Hepatotoxicity In clinical studies of abiraterone acetate (including the MAGNITUDE study), significant elevations of liver enzymes leading to treatment interruption or discontinuation have occurred (2% of patients in cohort 1 experienced dose modifications, and one patient (0.5%) discontinued treatment) (see 8 Adverse Reactions). Serious hepatotoxicity (including fatal outcomes) has been reported in post-marketing experience with abiraterone acetate monotherapy (see ZYTIGA). ® Product Monograph).

[0777] Serum aminotransferase (ALT) and total bilirubin levels should be measured before starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity occur, serum ALT and bilirubin levels should be measured immediately. AKEEGA should be discontinued if ALT or AST levels exceed five times the upper limit of normal (ULN) or bilirubin levels exceed three times the ULN at any time. ™ Treatment and close monitoring of liver function are necessary. For patients with concurrent elevations of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN, and without biliary obstruction or other causes of this elevation, AKEEGA should be permanently discontinued. ™ .

[0778] Treatment can only be restarted at a reduced dose level after liver function tests have returned to the patient's baseline (see 4 Dosage and Administration). If a patient experiences severe hepatotoxicity (ALT or AST being twenty times the ULN) at any time during treatment, AKEEGA should be permanently discontinued. ™ Treatment. Patients with active or symptomatic viral hepatitis were excluded from clinical trials; therefore, there is no data to support AKEEGA. ™ Use within this population.

[0779] immunity In patients receiving abiraterone acetate monotherapy, there have been post-marketing reports of allergic reactions requiring rapid medical intervention (see ZYTIGA). ® Product Review) Monitoring and laboratory testing • Complete blood counts should be obtained before starting treatment, weekly for the first month, bi-weekly for the next two months, monthly for the first year thereafter, and then monthly for the remainder of treatment (see 4 Dosage and Administration).

[0780] • Serum aminotransferase and total bilirubin should be measured before starting treatment, every two weeks for the first three months of treatment, monthly for the first year thereafter, and then every month during the duration of treatment.

[0781] • Serum potassium should be monitored monthly during the first year, and then every month thereafter during the duration of treatment.

[0782] • Using AKEEGA ™ During treatment, blood pressure should be monitored weekly for at least the first two months, then monthly for the first year, and then every other month thereafter.

[0783] • For those using AKEEGA ™ For patients who develop hypokalemia during treatment, consider maintaining their potassium level at ≥4.0 mM (see 4 Dosage and Administration). • If a patient discontinues prednisone or prednisolone, caution and monitoring for adrenal insufficiency are advised. If AKEEGA is continued after discontinuation of corticosteroids... ™ Patients should be monitored for symptoms of mineralocorticoid overdose. For patients receiving prednisone or prednisolone treatment who are experiencing unusual stress, the dose of corticosteroids may need to be increased before, during, and after the stressful event.

[0784] Musculoskeletal Combining with radium dichloride increases fracture and mortality rates. AKEEGA is not recommended. ™ Combination therapy with radium dichloride. In a randomized clinical trial of asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer with bone metastases, the addition of radium-223 dichloride to abiraterone plus prednisone / prednisolone showed increased mortality and fracture incidence (see ZYTIGA). ® Product Monograph).

[0785] Myopathy / Rhabdomyolysis There have been reports of myopathy / rhabdomyolysis in patients receiving abiraterone acetate monotherapy (see ZYTIGA). ® (Product monograph). Caution is advised for patients who are concurrently using medications known to be associated with myopathy / rhabdomyolysis.

[0786] Nervous system Posterior reversible encephalopathy syndrome (PRES) Posterior reversible encephalopathy syndrome (PRES) is a rare, reversible neurological disorder that can present with rapidly evolving symptoms, including seizures, headache, altered mental status, visual disturbances or cortical blindness, with or without associated hypertension. Diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).

[0787] There have been reports of PRES occurring in patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who received niraparib monotherapy (see ZEJULA). ® Product Monograph).

[0788] If a PRES occurs, AKEEGA should be permanently discontinued. ™ Treatment should be provided, and appropriate medical management should be implemented.

[0789] Reproductive health: female and male potential It is still unclear about AKEEGA ™ The presence of components or their metabolites in semen. If the patient has had sexual intercourse with a pregnant woman or a woman of childbearing potential, AKEEGA... ™ During treatment and for three months after the last dose, condoms and another highly effective method of contraception should be used.

[0790] Animal studies have shown reproductive toxicity (see 7.1.1 Pregnant women).

[0791] • Fertility There is no information about AKEEGA yet. ™ Clinical data on the effects on fertility. In animal studies, niraparib or abiraterone acetate reduced male fertility, but these effects were reversible upon discontinuation of treatment (see 16 Nonclinical Toxicology).

[0792] • Risk of birth defects Based on the mechanism of action of the two components and animal studies of abiraterone acetate, AKEEGA ™ It carries a potential risk of fetal harm (see 16 Nonclinical Toxicology).

[0793] Special populations 1.1.1 Pregnant women AKEEGA ™ It is not approved for use in women (see 10.3 Pharmacokinetics).

[0794] No pregnant women have used AKEEGA. ™ Data. Based on the mechanism of action of the two components and animal studies of abiraterone acetate, AKEEGA... ™It carries a potential risk of fetal harm. No animal developmental and reproductive toxicology studies have been conducted on niraparib (see 16 Nonclinical Toxicology – Reproductive and Developmental Toxicology).

[0795] To avoid accidental contact, pregnant women or women who may be pregnant should not handle AKEEGA without protection (e.g., wearing gloves). ™ tablet.

[0796] 7.1.2 Breastfeeding period AKEEGA ™ It is not approved for use in women.

[0797] 7.1.3 Pediatrics (<18 years old) Health Canada has no available data; therefore, Health Canada has not approved the pediatric indication. 1.1.4 Elderly patients (≥65 years old) In the MAGNITUDE cohort 1, 70.9% of participants were ≥65 years old, and 26.5% were ≥75 years old. No overall differences in safety and efficacy of the niraparib and abiraterone acetate combination therapy were observed between these patients and younger participants. However, the possibility that older individuals (≥75 years old) may be more sensitive cannot be ruled out. Enhanced surveillance of older individuals (≥75 years old) could be recommended.

[0798] Adverse reactions Adverse Reactions Overview AKEEGA ™ The overall safety profile was based on data from a phase 3, randomized, double-blind, placebo-controlled study, MAGNITUDE Cohort 1 (HRR positive), in which patients received once-daily oral nirapaniga abiraterone acetate and prednisone (AAP) (n=212) or placebo plus AAP (n=211) as a monotherapy combination (see 14 Clinical Trials). The median duration of exposure to nirapaniga AAP was 13.8 months (range: 0–29). Baseline and disease characteristics included a median age of 69 years (range 43–100), racial distribution of 74% White, 16.5% Asian, 1.2% Black, and others or unreported (8.3%), and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0:66% and ECOG PS1:34%. At study enrollment, 83.5% of patients had bone involvement and 21.3% had visceral disease. All patients who had not previously undergone orchiectomy continued background androgen deprivation therapy with GnRH analogs.

[0799] Serious adverse events occurred in 36% of subjects treated with nirapaniga AAP and 25% of subjects treated with placebo plus AAP. Anemia (5.7%) was a serious adverse reaction reported in ≥2% of subjects receiving nirapaniga AAP.

[0800] Fatal adverse events occurred in 5.7% of subjects treated with nirapaniga AAP and 3.3% of subjects treated with placebo plus AAP. Fatal adverse reactions due to pneumonia occurred in 0.5% of subjects receiving nirapaniga AAP, but not in any subjects receiving placebo plus AAP.

[0801] In patients in the MAGNITUDE cohort 1, the most common adverse reactions of all grades with an incidence >20% were anemia, hypertension, constipation, fatigue, nausea, and thrombocytopenia. The most frequently observed grade ≥3 adverse reactions were anemia, hypertension, thrombocytopenia, neutropenia, and elevated serum alkaline phosphatase.

[0802] Discontinuation of dosing for any component of the combination therapy due to adverse events occurred in 43% of subjects treated with niraparib plus AAP and 23% of subjects treated with placebo plus AAP. In cohort 1, 22% of subjects required discontinuation of niraparib dosing and switched to abiraterone acetate monotherapy. The median duration of abiraterone acetate monotherapy was 102 days (range: 6;518). In the niraparib plus AAP group, the most common adverse events leading to dosing discontinuation were anemia (22%), thrombocytopenia (9%), and neutropenia (7%). The incidence of all other TEAEs leading to dosing discontinuation was <5%.

[0803] In cohort 1, dose reductions due to adverse events occurred in 27% of patients in the nirapaniga AAP group and 9.5% of subjects in the placebo plus AAP group. In the nirapaniga AAP group, the most common adverse reactions leading to dose reduction were anemia (13%), thrombocytopenia (3%), and fatigue (2%).

[0804] In Cohort 1, permanent discontinuation due to adverse events occurred in 10.8% of patients treated with nirapaniga AAP and 6.2% of patients treated with placebo plus AAP. In the nirapaniga AAP group, the most common adverse events leading to discontinuation were COVID-19 / COVID-19 pneumonia (2.8%) and anemia (2.4%).

[0805] Overall, AKEEGA ™ The safety and tolerability profiles are consistent with the known safety profiles of its two monotherapy drugs, and no new safety signals were identified.

[0806] Adverse reactions in clinical trials Clinical trials are conducted under very specific conditions. Therefore, the incidence of adverse reactions observed in clinical trials may not reflect the incidence observed in practice and should not be compared with the incidence in clinical trials of another drug. Adverse reaction information from clinical trials may help identify and estimate the incidence of adverse drug reactions in real-world use. In the MAGNITUDE study, nirapaniga AAP and AKEEGA were evaluated in cohorts 1 and 3, respectively. ™ Safety in mCRPC patients with HRR mutations (Table 3).

[0807] Table 3: Adverse drug responses in mCRPC patients with HRR gene mutations, cohort 1 (compared to placebo + AAP) Compared to niraparib + AAP, the incidence rate increased by ≥2%. *CTCAE = Common Terminology Standard for Adverse Events, Version 5.0 a Grouping terms for cardiac arrhythmias: tachycardia, palpitation, atrial fibrillation, sinus tachycardia, supraventricular premature contractions, atrial tachycardia, cardiac and respiratory arrest, ventricular premature contractions, atrial flutter, bradycardia, tachycardia, ventricular tachycardia b Grouping terms for thromboembolism (venous): embolism, pulmonary embolism, thrombosis, deep vein thrombosis, venous thrombosis Hematologic toxicity Hematologic toxicities (anemia, thrombocytopenia, and neutropenia), including laboratory test results, are the most common adverse reactions attributed to niraparib. These toxicities typically occur within the first two months of treatment.

[0808] In the MAGNITUDE study, the following hematological parameters were included as inclusion criteria: absolute neutrophil count (ANC) ≥1,500 cells / μL; platelet count ≥100,000 cells / μL and hemoglobin ≥9 g / dL.

[0809] •anemia In the MAGNITUDE study, anemia was the most common adverse reaction (46.2%) and the most frequently observed grade >3 event (28.3%). Anemia typically occurred early in treatment (median time to onset 57 days, range: 1; 636 days); however, 50% of these patients had persistent low-grade chronic anemia. Dosage discontinuation occurred in 22.2% of patients, and dose reduction occurred in 13%. 26% of patients received at least one anemia-related transfusion. Anemia led to treatment discontinuation in 2.4% of subjects.

[0810] • Thrombocytopenia In the MAGNITUDE study, 21.2% of treated patients reported thrombocytopenia, while 6.6% experienced grade 3 to 4 thrombocytopenia. The median time from first dose to first effect was 43 days. Thrombocytopenia was managed through dose modification (interruption in 9.4%, reduction in 2.8%) and platelet transfusion when appropriate (2.4%). Treatment discontinuation occurred in 0.5% of patients, and bleeding events occurred in 1.4% of patients.

[0811] • Neutropenia In the MAGNITUDE study, 14% of patients experienced neutropenia, with 6.6% reporting grade 3 to 4 neutropenia. The median time from the first dose to the first report of neutropenia was 50 days. Neutropenia led to treatment discontinuation in 6.6% of patients and dose reduction in 1.4%. In the MAGNITUDE study, 0.9% of patients had concurrent infections.

[0812] Non-hematological adverse reactions hypertension High blood pressure is AKEEGA ™ Adverse reactions to both components were assessed in all combination trials excluding patients with uncontrolled hypertension (persistent systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg). Hypertension was reported in 31% of patients, with 15% having grade ≥3. The median time to hypertension was 56 days.

[0813] Heart events In the MAGNITUDE study, the most common major adverse cardiovascular event [MACE (ischemic heart disease, heart failure)] was ischemic heart disease (1.9%), and heart failure was also reported in 1.9% of patients. In addition, arrhythmias were reported in 12.7% of patients.

[0814] Hepatotoxicity Hepatotoxicity has been identified as a significant, known risk of abiraterone acetate. Patients with moderate to severe hepatic impairment (NCI classification) and those with Child-Turcotte-Pugh class B and C were excluded from AKEEGA. ™ Beyond combinatorial studies.

[0815] In the MAGNITUDE study, patients with baseline hepatitis or significantly abnormal liver function tests (serum total bilirubin ≤1.5×ULN or direct bilirubin ≤1×ULN, and AST or ALT ≤3×ULN) were excluded.

[0816] In the MAGNITUDE study, the overall incidence of hepatotoxicity was 12% in both groups. Grade 3 events occurred in 1.4% of patients, and only one patient (0.5%) experienced a Grade 4 event. The incidence of severe adverse events (SAEs) was 0.9%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 30 days. Hepatotoxicity was managed by dose interruption in 1.4% of patients and by dose reduction in 0.9% of patients. One patient (0.5%) in the MAGNITUDE study discontinued treatment due to hepatotoxicity.

[0817] Less common adverse reactions in clinical trials The following accepts Nirapani AAP or AKEEGA ™ The reported incidence of clinically significant adverse events in treated patients was less than 1%, and was higher than that in placebo plus AAP: Heart disease: QT interval prolongation Infectious and invasive diseases: urosepsis, conjunctivitis Study: Elevated γ-glutamyltransferase Metabolic and nutritional disorders: hypertriglyceridemia Skin and subcutaneous tissue diseases: photosensitivity Abnormal laboratory test results: hematological, clinical chemistry and other quantitative data Table 4 presents the worsening of hematological and chemical laboratory abnormalities from baseline in placebo-controlled cohort 1 of the MAGNITUDE study.

[0818] Table 4: Summary of laboratory abnormalities that worsened from baseline in patients treated with nirapaniga AAP (incidence higher than placebo+) AAP); Queue 1: All HRR security analysis sets (MAGNITUDE) Post-marketing adverse reactions At the time of approval, the issues discovered post-market were not identified.

[0819] Drug Interactions 1.2 Overview of Drug Interactions AKEEGA has not been used yet. ™ Conduct clinical trials to evaluate drug interactions. (At AKEEGA) ™ The interactions identified in studies of the individual components (niraparib or abiraterone acetate) may be related to AKEEGA. ™ The interactions that occur.

[0820] Niraparib (For an overview of drug interactions, see ZEJULA) ® Product Review) Formal drug interaction studies with niraparib have not yet been conducted.

[0821] In vitro studies CYP substrate: Niraparib is an in vivo substrate for carboxylesterase (CE) and UDP-glucuronyltransferase (UGT).

[0822] CYP Inhibition: Neither niraparib nor its major primary metabolite M1 is an inhibitor of CYP1A1 / 2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. At relevant niraparib concentrations, the potential for CYP3A4 inhibition at the intestinal level has not been established. Therefore, caution is advised when niraparib is combined with active substances that are metabolized in a manner dependent on CYP3A4.

[0823] CYP induction: Neither niraparib nor M1 is a CYP3A4 inducer in vitro. Niraparib weakly induces CYP1A2 in vitro. Therefore, caution is advised when niraparib is combined with active substances that are metabolized in a manner dependent on CYP1A2.

[0824] UGT inhibition: In vitro, niraparib did not show inhibitory effects on UGT subtypes (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) at concentrations up to 200 μM. Therefore, the likelihood of niraparib producing clinically relevant inhibition of UGT is extremely low.

[0825] Transport system inhibition: Niraparib is a weak inhibitor of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), with an IC50 value of [missing value]. 50 The concentrations were 5.8 μM and 161 μM, respectively, but neither inhibited the bile salt export pump (BSEP). The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or multidrug and toxin efflux protein (MATE)-1 or -2. Neither niraparib nor M1 is an inhibitor of organic anion transport peptides 1B1 (OATP1B1), 1B3 (OATP1B3), or organic anion transport proteins 1 (OAT1), 3 (OAT3), or organic cation transport protein 2 (OCT2).

[0826] Niraparib is an inhibitor of MATE-1 and -2, IC50 50 The concentrations were 0.18 μM and ≤0.14 μM, respectively (see 9.4 Drug-Drug Interactions). In vitro, niraparib weakly inhibits organic cation transporter 1 (OCT1), with an IC50 concentration of 0.18 μM and ≤0.14 μM, respectively. 50 = 34.4μM.

[0827] Caution is advised when niraparib is combined with active substances that are transported via OCT1 uptake.

[0828] Transport system substrates: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE-1 or 2. Metabolite M1 is not a substrate of P-gp, BCRP, BSEP, or MATE-1 and 2. Neither niraparib nor M1 is a substrate of organic anion transport peptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2).

[0829] Abiraterone acetate (For an overview of drug interactions, see ZYTIGA) ® Product Review) In vitro studies In vitro studies have shown that CYP3A4 (see 9.4 Drug-Drug Interactions) and sulfotransferase 2A1 (SULT2A1) are the main isoenzymes involved in abiraterone metabolism.

[0830] CYP Inhibition: Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2C8 and CYP2D6 (see 9.4 Drug-Drug Interactions). In vitro studies using human liver microsomes have shown that abiraterone is a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4 / 5 (these in vitro findings have not been confirmed by clinical DDI studies).

[0831] OATP1B1 substrate: In vitro, abiraterone and its major metabolite have been shown to inhibit hepatic uptake of the transporter OATP1B1, potentially increasing the concentration of the drug eliminated via OATP1B1. No clinical data are available to confirm transporter-based interactions.

[0832] Drug-behavioral interactions In exposure to niraparib monotherapy (see ZEJULA) ® Product monographs) and AKEEGA ™ Photosensitivity reactions have been observed in patients receiving combination therapy. Patients should be informed regarding AKEEGA. ™ Avoid sun exposure as much as possible during treatment.

[0833] 1.4 Drug-Drug Interactions Other drug components affect AKEEGA ™ potential CYP3A4 inducer: Based on in vitro data, abiraterone is a substrate of CYP3A4. In a clinical pharmacokinetic interaction study in healthy subjects, after prior treatment with a potent CYP3A4 inducer (rifampin, 600 mg daily for 6 days), a single dose of abiraterone acetate 1,000 mg was administered, and the mean plasma AUC of abiraterone was [data missing].∞ Reduced by 55%. Avoid AKEEGA. ™ A potent CYP3A4 inducer was used during treatment.

[0834] CYP3A4 inhibitors: In a clinical pharmacokinetic interaction study, healthy subjects were given a potent CYP3A4 inhibitor, ketoconazole, 400 mg daily for 6 days. Following a single dose of abiraterone acetate 1,000 mg on day 4, no clinically meaningful effect on the pharmacokinetics of abiraterone was demonstrated.

[0835] AKEEGA ™ Potential to affect other drugs CYP2D6 substrate: In a clinical study determining the effect of abiraterone acetate (gaprednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased by approximately 200%. The AUC of dextromethorphan's active metabolite, dextromethorphanone, is also shown. 24 It increased by approximately 33%. When AKEEGA ™ Caution is advised when using this medication concurrently with drugs that are activated or metabolized by CYP2D6, particularly those with a narrow therapeutic index. Consideration should be given to reducing the dose of CYP2D6-metabolized drugs with a narrow therapeutic index.

[0836] CYP2C8 substrates: In a clinical pharmacokinetic interaction study in healthy subjects, when a single dose of pioglitazone was co-administered with a single dose of 1,000 mg abiraterone acetate, the AUC of pioglitazone increased by 46%, while the AUCs of the active metabolites M-III and M-IV of the CYP2C8 substrate pioglitazone each decreased by 10%. If a CYP2C8 substrate with a narrow therapeutic index is co-administered with AKEEGA... ™ When used concurrently, patients should be monitored for signs of substrate-related toxicity.

[0837] The drugs listed in Table 5 are related to AKEEGA. ™ The interaction between them.

[0838] Table 5: Identified or Potential Drug-Drug Interactions CT* = Abiraterone acetate clinical trial, T* = theoretical value AKEEGA has not yet been studied. ™ Drug interactions with vaccines or immunosuppressants.

[0839] Data on the combination of niraparib and cytotoxic drugs is limited. If AKEEGA ™ Caution should be exercised when using this medication in combination with vaccines, immunosuppressants, or other cytotoxic drugs. (In AKEEGA) ™The safety of immunization with live or attenuated live vaccines during treatment and the immune response to any vaccine are unclear.

[0840] Drug-food interactions AKEEGA ™ Do not take with food (see 4 Dosage and Administration, and 10.3 Pharmacokinetics). Taking with food may lead to AKEEGA. ™ The potential risks of increased and highly variable systemic exposure.

[0841] Drug-herb interactions Avoid using it at the same time as St. John's wort (St. John's wort) or products containing St. John's wort.

[0842] Drug-Laboratory Testing Interactions The interaction with laboratory testing has not yet been determined.

[0843] Clinical Pharmacology Mechanism of action Niraparib and Abiraterone Acetate tablets are a dual-action tablet combination containing niraparib (an inhibitor of poly(ADP-ribose) polymerases (PARP) (PARP-1 and PARP-2, enzymes that play a role in DNA repair) and abiraterone prodrug (abiraterone acetate is converted into abiraterone in the body, an inhibitor of androgen biosynthesis). This combination targets two oncogenic dependencies in patients with mCRPC and HRR gene alterations.

[0844] In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzyme activity and increased PARP-DNA complex formation, leading to DNA damage, apoptosis, and cell death. Increased niraparib-induced cytotoxicity was observed in tumor cell lines with or without BRCA1 / 2 deficiency. Niraparib reduced tumor growth in mouse xenograft models of BRCA1 / 2-deficient human cancer cell lines, patient-derived xenograft tumor models with homologous recombination deficiency and BRCA1 / 2 mutant or wild-type, and tumors with BRCA wild-type and no detectable homologous recombination deficiency.

[0845] Abiraterone acetate is converted to abiraterone in vivo, which selectively inhibits 17α-hydroxylase / C17,20-lyase (CYP17). CYP17 is expressed in testicular, adrenal, and prostate tumor tissues and is essential for androgen biosynthesis in these tissues. CYP17 catalyzes the conversion of pregnenolone and progesterone to the testosterone precursors DHEA and androstenedione via 17α-hydroxylation and cleavage of the C17,20 bond.

[0846] Androgen-sensitive prostate cancer responds to treatments that lower androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, reduce androgen production in the testes but do not affect androgen production in the adrenal glands or tumors. When combined with GnRH agonists (or orchiectomy), treatment with abiraterone lowers serum testosterone to undetectable levels (using commercially available assays).

[0847] In preclinical mouse models of prostate cancer, the combination of niraparib and abiraterone acetate demonstrated superior efficacy compared to either active ingredient alone. This was demonstrated in both the BRCA1 / 2 wild-type VCaP model and the BRCA2 mutant LuCaP 96 model.

[0848] Pharmacodynamics Since Niraparib and Abiraterone Acetate Tablets contain both niraparib and abiraterone acetate, the pharmacodynamic effects of each component should be considered.

[0849] Cardiac electrophysiology Niraparib (see ZEJULA for pharmacodynamics) ® Product Review) The potential of niraparib to prolong the QTc interval was evaluated in a randomized, placebo-controlled study of cancer patients (367 patients received niraparib and 179 patients received placebo). No significant changes in the mean QTc interval (>20 ms) were detected after treatment with niraparib 300 mg once daily in the study.

[0850] Abiraterone acetate (see ZYTIGA for pharmacodynamics) ® Product Review) In a multicenter, open-label, non-control, single-arm ECG assessment study, 33 patients with metastatic castration-resistant prostate cancer who underwent medical castration (N=28) or surgical castration (N=5) were studied. Series of ECGs were recorded at baseline and on day 1 of the first and second 28-day treatment cycles (abiraterone acetate 1 g / day plus prednisone 5 mg twice daily). At steady state on day 1 of cycle 2, the QTc interval was significantly shortened at most time points, with the maximum reduction relative to baseline at 24 hours post-dose being a mean of -10.7 (90% CI -14.8, -6.5) ms.

[0851] Androgen deprivation is associated with QTc prolongation. In this study, the mean baseline QTc interval was 435 to 440 ms, and 57.6% of the subjects had a baseline QTc value >450 ms before starting abiraterone acetate treatment. Since the subjects in this trial were already under androgen deprivation, these results cannot be extrapolated to non-castrated individuals.

[0852] Cardiovascular effects (see ZEJULA for pharmacodynamics) ® Product Review) Niraparib (see ZEJULA for pharmacodynamics) ® Product Review) Niraparib carries the potential risk of affecting patients' pulse rate and blood pressure, which may be related to its pharmacological inhibition of dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT).

[0853] Based on the PRIMA study (NCT02655016) in patients with advanced ovarian cancer, the mean increases in pulse rate and blood pressure from baseline were higher in the niraparib group than in the placebo group in most study assessments. During treatment, the mean maximum increase in pulse rate from baseline was 22.4 beats / min in the niraparib group and 14.0 beats / min in the placebo group. During treatment, the mean maximum increase in systolic blood pressure from baseline was 24.4 mmHg in the niraparib group and 19.6 mmHg in the placebo group. During treatment, the mean maximum increase in diastolic blood pressure from baseline was...

Claims

1. A pharmaceutical product approved for marketing by a government regulatory agency for at least one indication, wherein the pharmaceutical product comprises niraparib and abiraterone acetate.

2. The pharmaceutical product of claim 1, wherein the at least one approved indication is metastatic castration-resistant prostate cancer (mCRPC).

3. The pharmaceutical product of claim 1 or 2, wherein the pharmaceutical product is indicated for use in combination with prednisone for the treatment of patients with harmful or suspected harmful breast cancer mutation (BRCAm) mCRPC detected by a test.

4. The pharmaceutical product of claim 3, wherein the pharmaceutical product is administered for a once-daily oral delivery of a dose of 200 mg niraparib and 1,000 mg abiraterone acetate, and is administered in combination with a daily dose of 10 mg prednisone.

5. The pharmaceutical product of claim 3, wherein in the event of myelosuppression with: (i) platelet count < 100,000 / mcL, or (ii) neutrophil count < 1,000 / mcL or hemoglobin count < 8 g / dL; or in the event of other non-hematologic Grade 3 or 4 adverse reactions, the pharmaceutical product is administered orally once daily at a reduced dose of 100 mg niraparib and 1,000 mg abiraterone acetate.

6. The pharmaceutical product of any one of claims 3 to 5, wherein the pharmaceutical product is administered on an empty stomach.

7. The pharmaceutical product of any one of claims 3 to 6, wherein no food is taken within two hours before and one hour after taking the pharmaceutical product.

8. The pharmaceutical product of any one of claims 3 to 7, wherein the patient is concurrently receiving gonadotropin-releasing hormone (GnRH) analog therapy, or the patient has received bilateral orchiectomy.

9. The pharmaceutical product of claim 8, wherein the GnRH analog is selected from triptorelin, nafarelin, goserelin, leuprolide or leuprorelin, histrelin, gonadorelin, and buserelin.

10. The pharmaceutical product of any one of claims 3 to 9, wherein the pharmaceutical product is not administered to a patient with moderate or severe hepatic impairment.

11. The pharmaceutical product of any one of claims 3 to 10, wherein the pharmaceutical product is not co-administered with the CYP3A4 inducer rifampin.

12. The pharmaceutical product of any one of the preceding claims, wherein the pharmaceutical product comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and (i) 100 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (regular strength); or (ii) 50 mg niraparib and 500 mg abiraterone acetate in an oral dosage form (lower strength).

13. The pharmaceutical product of any one of claims 4 to 12, wherein in patients with harmful or suspected harmful BRCAm mCRPC detected by an approved test, the pharmaceutical product elicits a median overall survival (OS) of 30.4 months with a hazard ratio (HR) of 0.788 (95% CI: 0.554, 1.120). ​ ​ 14. The drug product of claim 13, wherein the HR for median OS is 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from the group consisting of prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (Alk Phos), age, Eastern Cooperative Oncology Group (ECOG) performance status, number of bone lesions, and visceral disease.

15. The drug product of any one of claims 4 to 14, wherein the drug product elicits an improved median time to symptom progression (TSP) when compared to patients receiving placebo and abiraterone acetate plus prednisone, HR 0.562 (95% CI: 0.371, 0.849), in patients with deleterious or suspected deleterious BRCAm mCRPC as tested.

16. The drug product of any one of claims 4 to 15, wherein the drug product elicits an improved median time to cytotoxic chemotherapy (TCC) when compared to patients receiving placebo and abiraterone acetate plus prednisone, HR 0.598 (95% CI: 0.387, 0.924), in patients with deleterious or suspected deleterious BRCAm mCRPC as tested.

17. The drug product of any one of claims 4 to 16, wherein the drug product elicits a median radiographic progression-free survival (rPFS) of 19.5 months, HR 0.553 (95% CI: 0.392, 0.782), in patients with deleterious or suspected deleterious BRCAm mCRPC as tested.

18. The drug product of any one of claims 1 to 17, wherein the drug product comprises 159.40 mg of niraparib mesylate monohydrate equivalent to 100 mg of niraparib free base as active ingredient, and 500 mg of abiraterone acetate.

19. The drug product of any one of claims 1 to 17, wherein the drug product comprises 79.70 mg of niraparib mesylate monohydrate equivalent to 50 mg of niraparib free base as active ingredient, and 500 mg of abiraterone acetate.

20. The drug product of any one of claims 12 to 19, wherein the pharmaceutical composition is an oral dosage form selected from the group consisting of film-coated tablets, tablets, capsules, granules, and sachets.

21. The drug product of claim 20, wherein the pharmaceutical composition is a film-coated tablet further comprising colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate; and a film coating.

22. The drug product of claim 21, wherein the film-coated tablet comprises 100 mg niraparib and 500 mg abiraterone acetate; and the film coating comprises iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monostearate, polyvinyl alcohol, talc, and titanium dioxide.

23. The drug product of claim 21, wherein the film-coated tablet comprises 50 mg niraparib and 500 mg abiraterone acetate; and the film coating comprises iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulfate, glyceryl monostearate, polyvinyl alcohol, talc, and titanium dioxide.

24. The drug product of any one of the preceding claims, wherein the drug product is approved for marketing in the European Economic Area (EEA) or Canada.

25. The drug product of any one of the preceding claims, wherein the drug product is a generic drug, an ANDA, an sNDA, an NDA product, or a 505(b)(2) drug product.

26. A method for treating a mCRPC patient who tests positive for a harmful or suspected harmful BRCAm, the method comprising administering to the patient the drug product as defined in any one of the preceding claims in combination with prednisone.

27. The method for treating mCRPC of claim 26, wherein the method of treatment comprises once daily oral administration of the drug product containing 200 mg niraparib and 1,000 mg abiraterone acetate, concurrently with separate daily administration of 10 mg prednisone, until disease progression or unacceptable toxicity occurs.

28. The method for treating mCRPC of claim 26, wherein the method of treatment comprises once daily oral administration of a reduced dose of the drug product containing 100 mg niraparib and 1,000 mg abiraterone acetate, concurrently with separate daily administration of 10 mg prednisone, in the presence of myelosuppression with: (i) platelet count < 100,000 / mcL, or (ii) neutrophil count < 1,000 / mcL or hemoglobin count < 8 g / dL; or in the presence of other non-hematologic Grade 3 or 4 adverse reactions.

29. The method for treating mCRPC of any one of claims 26 to 28, wherein the method of treatment comprises improving the median OS to 30.4 months, HR 0.788 (95% CI: 0.554, 1.120).

30. The method for treating mCRPC of claim 29, wherein the median OS is further improved, HR 0.663 (95% CI: 0.464, 0.947), after multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from the group consisting of PSA, LDH, Alk Phos, age, ECOG grade, number of bone lesions, and visceral disease.

31. The method for treating mCRPC of any one of claims 26-30, wherein the treatment comprises a median TSP improvement with an HR of 0.562 (95% CI: 0.371, 0.849).

32. The method for treating mCRPC of any one of claims 26-31, wherein the treatment comprises a median TCC improvement with an HR of 0.598 (95% CI: 0.387, 0.924).

33. The method for treating mCRPC of any one of claims 26-32, wherein the treatment comprises a median rPFS improvement to 19.5 months with an HR of 0.553 (95% CI: 0.392, 0.782).

34. A method of marketing a drug product comprising niraparib and abiraterone acetate as defined in any one of claims 1-25, the method comprising marketing such drug product.

35. The method of marketing of claim 34, wherein the drug product is a generic drug, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product.

36. The method of marketing of claim 34 or 35, wherein the reference formulation of such drug product improves OS, rPFS, TCC, TSP, or TPP.

37. The method of marketing of claim 36, wherein the median OS is 30.4 months with an HR of 0.788 (95% CI: 0.554, 1.120).

38. The method of marketing of claim 37, wherein the HR for the median OS is 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from the group consisting of PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and visceral disease.

39. The method of marketing of any one of claims 36-38, wherein the median TSP is improved with an HR of 0.562 (95% CI: 0.371, 0.849).

40. The method of marketing of any one of claims 36-39, wherein the median TCC is improved with an HR of 0.598 (95% CI: 0.387, 0.924).

41. The method of marketing of any one of claims 36-40, wherein the median rPFS is 19.5 months with an HR of 0.553 (95% CI: 0.392, 0.782).

42. A method of providing for marketing a drug product comprising niraparib and abiraterone acetate as defined in any one of claims 1-25, the method comprising providing for marketing such drug product.

43. The method of making available for sale of claim 42, wherein the drug product is a generic drug, an ANDA drug product, a supplemental New Drug Application drug product, an NDA product, or a 505(b)(2) drug product.

44. The method of making available for sale of claim 42 or 43, wherein the reference formulation for such drug product improves OS, rPFS, TCC, TSP, or TPP.

45. The method of making available for sale of claim 44, wherein the median OS is 30.4 months with an HR of 0.788 (95% CI: 0.554, 1.120).

46. The method of making available for sale of claim 45, wherein the HR for the median OS is 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from the group consisting of PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and visceral disease.

47. The method of making available for sale of any one of claims 44 to 46, wherein the median TSP is improved with an HR of 0.562 (95% CI: 0.371, 0.849).

48. The method of making available for sale of any one of claims 44 to 47, wherein the median TCC is improved with an HR of 0.598 (95% CI: 0.387, 0.924).

49. The method of making available for sale of any one of claims 44 to 48, wherein the median rPFS is 19.5 months with an HR of 0.553 (95% CI: 0.392, 0.782).

50. The drug product of any one of the preceding claims 1 to 25 for use in a method of treating a mCRPC patient who tests positive for a deleterious or suspected deleterious BRCAm, the method comprising administering the drug product in combination with prednisone.

51. The drug product of any one of the preceding claims 1 to 25 for use in the method of claim 50, wherein the method of treatment comprises once-daily oral administration of a dose containing 200 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product, and 10 mg of prednisone, until disease progression or unacceptable toxicity occurs.

52. The drug product of any one of the preceding claims 1 to 25 for use in the method of claim 50, wherein the method of treatment comprises once-daily oral administration of a reduced dose containing 100 mg of niraparib and 1,000 mg of abiraterone acetate of the drug product, and 10 mg of prednisone, in the presence of myelosuppression with: (i) platelet count < 100,000 / mcL, or (ii) neutrophil count < 1,000 / mcL or hemoglobin count < 8 g / dL; or in the presence of other non-hematologic Grade 3 or 4 adverse reactions.

53. The drug product of any one of the preceding claims 1 to 25, for use in a method of any one of claims 50 to 52, wherein the treatment method comprises improving the median OS to 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

54. The drug product of any one of the preceding claims 1 to 25, for use in the method of claim 53, wherein the median OS is further improved with a Hazard Ratio (HR) of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusting for external validation and clinically relevant baseline prognostic factors selected from the group consisting of PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and visceral disease.

55. The drug product of any one of the preceding claims 1 to 25, for use in a method of any one of claims 50 to 54, wherein the treatment comprises improving the median TSP with a Hazard Ratio (HR) of 0.562 (95% CI: 0.371, 0.849).

56. The drug product of any one of the preceding claims 1 to 25, for use in a method of any one of claims 50 to 55, wherein the treatment comprises improving the median TCC with a Hazard Ratio (HR) of 0.598 (95% CI: 0.387, 0.924).

57. The drug product of any one of the preceding claims 1 to 25, for use in a method of any one of claims 50 to 56, wherein the treatment comprises improving the median rPFS to 19.5 months with a Hazard Ratio (HR) of 0.553 (95% CI: 0.392, 0.782).

58. A drug product comprising niraparib and abiraterone acetate for use with prednisone or prednisolone in a method for treating adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA 1 / 2 mutations (germline and / or somatic mutations) who are chemotherapy-naive; wherein BRCA positive status is determined using a validated test method; wherein the daily dose of the drug product is 200 mg of niraparib and 1,000 mg of abiraterone acetate and the daily dose of prednisone or prednisolone is 10 mg until disease progression or unacceptable toxicity occurs; wherein the treatment comprises improving the median overall survival (OS) to 30.4 months with a Hazard Ratio (HR) of 0.788 (95% CI: 0.554, 1.120).

59. The drug product for use according to claim 58, wherein the median OS is further improved with an HR of 0.663 (95% CI: 0.464, 0.947) after multivariate Cox regression analysis adjusted for external validation and clinically relevant baseline prognostic factors selected from the group consisting of PSA, LDH, Alk Phos, age, ECOG grade, bone lesion number, and visceral disease.

60. The drug product for use according to claim 58 or 59, wherein the treatment comprises improving the median TSP with an HR of 0.562 (95% CI: 0.371, 0.849).

61. The drug product for use according to any one of claims 58 to 60, wherein the treatment comprises improving the median TCC with an HR of 0.598 (95% CI: 0.387, 0.924).

62. The drug product for use according to any one of claims 58 to 61, wherein the treatment comprises improving the median rPFS to 19.5 months with an HR of 0.553 (95% CI: 0.392, 0.782).

Images