Treatment of metastatic castration-resistant prostate cancer with niraparib

Abstract

The present invention relates to a method of improving the efficacy of a treatment for line 2+ metastatic castration-resistant prostate cancer (mCRPC) with a biallelic DNA repair defect in a human male, wherein the biallelic DNA repair defect is selected from i) BRCA (BRCA1, BRCA2, or a combination thereof); ii) non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof); or iii) any combination thereof, and wherein the human male has received prior taxane-based chemotherapy and androgen receptor (AR) targeted therapy, the method of improving the efficacy of treatment comprising administering to the human male a once daily oral dose of 300 mg niraparib.

Description

[Technical field]

[0001] TECHNICAL FIELD OF THEINVENTION The present disclosure relates to methods of improving therapeutic efficacy in patients with metastatic castration-resistant prostate cancer.

[0002] 2. Background of the Invention Prostate cancer is the most common non-cutaneous malignancy in men and the second leading cause of cancer deaths in men in the Western world.

[0003] Prostate cancer is caused by the uncontrolled growth of abnormal cells in the prostate. When prostate cancer tumors develop, androgens (male hormones from the testes), such as testosterone, promote the growth of prostate cancer. In its early stages, localized prostate cancer is often treatable by localized therapy, including, for example, surgical removal of the prostate and radiation therapy. However, when localized therapy fails to cure prostate cancer, as is the case in at least one-third of men, the disease progresses to incurable metastatic disease (i.e., disease in which the cancer spreads from one part of the body to another).

[0004] Current treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) that improve survival and limit progression include taxane-based chemotherapy and androgen receptor-targeted agents, such as abiraterone acetate plus prednisone, enzalutamide, or radium-223.

[0005] Platinum-based chemotherapy has been tested in numerous clinical studies in molecularly unselected prostate cancer patients with limited results and significant toxicity.

[0006] Niraparib is an orally available, highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymers.

[0007] PARP is an enzyme involved in the repair of DNA single-strand breaks (SSBs) through a process called base excision repair. PARP inhibition results in the accumulation of unrepaired SSBs, leading to stalled and collapsed replication forks, which in turn results in double-stranded breaks (DSBs). Normally, DSBs are repaired by homologous recombination (HR). If unrepaired, DSBs result in cell death. When tumor cells with DNA repair defects involving the HR pathway (e.g., breast cancer allele [BRCA]-1 / 2) are treated with PARP inhibitors, they are unable to efficiently and accurately repair DSBs, resulting in a synthetic lethal state. In men with metastatic castration-resistant prostate cancer (mCRPC), tumors with DNA repair defects account for approximately 20%-30% of sporadic cancers.

[0008] Improved methods of treating prostate cancer in patients who either initially fail to respond or become refractory to existing treatments are needed.

[0009] Summary of the Invention The objective of the present invention is to improve the efficacy of treating line 2+ mCRPC with biallelic DNA repair defects selected from i) BRCA (BRCA1, BRCA2, or a combination thereof), ii) non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof), or iii) any combination thereof, in human males who have previously received taxane-based chemotherapy and AR-targeted therapy.

[0010] The aim of the present invention is to improve the efficacy of treatment of mCRPC in patients with more advanced stage disease or severe disease burden, e.g. visceral disease (clinical manifestations of mCRPC with predominant pulmonary and hepatic involvement), which carries a particularly grim prognosis.

[0011] It is an object of the present invention to improve the efficacy of treatment of mCRPC in patients who are heavily pre-treated and have no or few other effective treatment options available, e.g., third, fourth or fifth line or beyond patients.

[0012] The objective of the present invention is to provide an improved treatment for mCRPC that results in a stable improvement in the Health Related Quality of Life (HRQoL) in patients, which is an extraordinary outcome in a hard-to-treat population.

[0013] The present invention relates to a method of improving the efficacy of a treatment for line 2+ metastatic castration-resistant prostate cancer (mCRPC) with a biallelic DNA repair defect in a human male, wherein the biallelic DNA repair defect is selected from i) BRCA (BRCA1, BRCA2, or a combination thereof); ii) non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof); or iii) any combination thereof, and wherein the human male has received prior taxane-based chemotherapy and androgen receptor (AR) targeted therapy, the method of improving the efficacy of treatment comprising administering to the human male a once daily oral dose of 300 mg niraparib.

[0014] The improved efficacy is reflected in a median Overall Survival (OS) of approximately 12 months with a 95% Confidence Interval (CI).

[0015] In one embodiment, the human male has a BRCA DNA repair defect and the median OS is about 13 months (95% CI).

[0016] In one embodiment, the human male has a non-BRCA DNA repair defect and the median OS is about 10 months (95% CI).

[0017] The improved efficacy was also reflected in a median radiographic progression-free survival (rPFS) of approximately 5.6 months (95% CI).

[0018] In one embodiment, the human male has a BRCA DNA repair defect and the rPFS is about 8.1 months (95% CI).

[0019] In one embodiment, the human male has a BRCA DNA repair defect, and the improved efficacy is an Objective Response Rate (ORR) of about 34.2% (95% CI).

[0020] The improved efficacy was also reflected by a median duration of objective response of approximately 5.55 months (95% CI).

[0021] The improved efficacy was also seen in the time to radiological progression of approximately 5.8 months (95% CI).

[0022] In one embodiment, the human male has a BRCA DNA repair defect and the time to radiological progression is about 8.08 months (95% CI).

[0023] The improved efficacy is also reflected in the median time to PSA progression of approximately 4.6 months (95% CI).

[0024] The improved efficacy was also reflected in the median time to symptomatic skeletal-related events of approximately 13 months (95% CI).

[0025] The improved efficacy was also reflected by a Circulating Tumor Cells (CTC) response rate of approximately 18% (95% CI).

[0026] In one embodiment, the human male has a BRCA DNA repair defect and the CTC response rate is about 24% (95% CI).

[0027] In one embodiment, the human male has a non-BRCA DNA repair defect and the CTC response rate is about 9% (95% CI).

[0028] In any one of the methods presented herein, the taxane-based chemotherapy is docetaxel, paclitaxel, or cabazitaxel.

[0029] In any one of the methods provided herein, the AR targeted therapy includes i) surgical castration (orchiectomy), and / or ii) medical castration selected from the group consisting of Luteinizing Hormone-Releasing Hormone (LHRH) agonists, such as leuprolide or leuprolide, goserelin, triptorelin, histrelin, nafarelin, gonadorelin, buserelin, and the like, LHRH antagonists such as degarelix, relugolix, and the like, abiraterone acetate (Zytiga®), ketoconazole, antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, and the like, and other androgen suppressing drugs such as estrogen, diethylstilbestrol, and the like.

[0030] In any one of the methods presented herein, niraparib is in the salt form of tosylate monohydrate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate.

[0031] The invention also relates to administration of a once daily oral dosage of 300 mg of niraparib for use in any one of the methods presented herein for improving the efficacy of treating line 2+ metastatic castration-resistant prostate cancer (mCRPC) with biallelic DNA repair abnormalities in a human male, wherein the biallelic DNA repair abnormalities are selected from i) BRCA (BRCA1, BRCA2, or a combination thereof); ii) non-BRCA (ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof); or iii) any combination thereof, and wherein the human male has previously been treated with taxane-based chemotherapy and androgen receptor (AR) targeted therapy. [Brief description of the drawings]

[0032] [Figure 1] Kaplan-Meier plot of overall survival is shown, ITT is the analysis subject population. ITT: BRCA or non-BRCA subjects, BRCA: biallelic BRCA1 or BRCA2 or germline BRCA, non-BRCA, biallelic in ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. [Diagram 2] Kaplan-Meier plot of rPFS is shown, where ITT is the analysis population. ITT: BRCA or non-BRCA subjects, BRCA: biallelic BRCA1 or BRCA2 or germline BRCA, non-BRCA, biallelic in ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. [Diagram 3] Kaplan-Meier plot of time to radiological progression is shown, where ITT is the analysis population. ITT: BRCA or non-BRCA subjects, BRCA: biallelic BRCA1 or BRCA2 or germline BRCA, non-BRCA, biallelic in ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. [Figure 4]A waterfall plot of maximum change in PSA from baseline at any time in the study is shown, where ITT is the analysis subject population. Baseline represents a 50% decrease. Increase or decrease of 100% or more is set to 100%. B=BRCA, N=non-BRCA. ITT: BRCA subjects or non-BRCA subjects, BRCA: biallelic BRCA1 or BRCA2 or germline BRCA, non-BRCA, biallelic in ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2.

[0033] Detailed Description of the Invention The present invention may be more readily understood by reference to the following detailed description: It is to be understood that these inventions are not limited to the specific products, methods, conditions, or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing specific embodiments by way of example only, and is not intended to limit the invention as claimed.

[0034] The entire disclosure of each patent, patent application, and publication cited or described in this specification is hereby incorporated by reference.

[0035] As used above, and throughout this disclosure, the following terms and abbreviations shall be understood to have the following meanings, unless otherwise indicated:

[0036] In this disclosure, unless expressly stated otherwise, the singular forms "a," "an," and "the" include plural references and a reference to a given numerical value includes at least that given value. Thus, for example, a reference to "an ingredient" is a reference to one or more such ingredients and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a particular element "may be" X, Y, or Z, such use is not intended to exclude other options for that element in all instances.

[0037] When values ​​are expressed as approximations, by use of the antecedent "about," it is to be understood that the particular value forms another embodiment. As used herein, "about X," where X is a numerical value, preferably refers to ±10% of the stated value, inclusive. For example, the phrase "about 8" refers to values ​​from 7.2 to 8.8, inclusive, and as another example, the phrase "about 8%" refers to values ​​from 7.2% to 8.8%, inclusive.

[0038] Where present, all ranges are inclusive and combinable. For example, when listing a range of "1 to 5," the listed range should be interpreted as including 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. It should be noted that when a list of alternatives is explicitly provided, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when a range of "1 to 5" is described, such a description may support a situation in which any of 1, 2, 3, 4, or 5 is excluded. Thus, a description of "1 to 5" may support "1 and 3 to 5, but not 2," or simply "2 is not included."

[0039] List of term abbreviations

[0040] [Table 1-1]

[0041] [Table 1-2]

[0042] "Treat," "treating," and "treatment" refer to an intervention aimed at ameliorating cancer by inhibiting, slowing, slowing the rate of, or halting the progression of cancer. Unless otherwise indicated, the terms "treat" and "treatment" refer to the totality of the effects described, although in other embodiments, the terms may also refer to any one of the effects described, or to the exclusion of at least one effect.

[0043] By "improving efficacy" is meant achieving a better measure of one or more clinical outcomes or endpoints related to efficacy when compared to the same measure when treated with the Standard Of Care (SOC) or other therapy available in the art for the same or comparable cohort of patients and clinical stage of disease.

[0044] By "therapeutically effective amount" or "effective amount" is meant an amount of a therapeutic agent effective to treat prostate cancer.

[0045] By "safe therapeutic" is meant an amount of a therapeutic agent that is safe for treating prostate cancer.

[0046] "Once-daily" refers to a dosing regimen in which two or more dosage forms are administered once a day (qd), i.e., within a short period of time in a day. For example, when two, three, or four niraparib dosage forms are administered once a day, they are administered simultaneously or within one minute, two minutes, five minutes, one hour, or within the maximum period that does not impair the pharmacokinetics and pharmacodynamics of niraparib achieved in the clinical trial subjects of the present invention. "Once-daily" is used in contrast to "multiple-daily," which refers to two or more dosage forms administered twice a day (bid), three times a day (tid), four times a day (qid), etc.

[0047] The term "pharmaceutical acceptable" means generally safe, non-toxic, and not biologically or otherwise undesirable, and includes acceptable for human pharmaceutical use as well as veterinary use.

[0048] The term "androgen receptor" includes wild-type androgen receptor, as well as androgen-resistant AR and / or AR mutants associated with castration-resistant prostate cancer.

[0049] The term "taxane-based chemotherapy" includes, but is not limited to, docetaxel, paclitaxel, and cabazitaxel.

[0050] The term "AR-targeted therapy" refers to hormone treatment whose goal is to lower levels of male hormones called androgens in the body or to stop them from supporting prostate cancer growth. AR targeted therapy may be i) surgical castration (orchiectomy), or ii) medical castration by administration of luteinizing hormone releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH analogs) such as, but not limited to, leuprolide or leuprolide, goserelin, triptorelin, histrelin, nafarelin, gonadorelin, buserelin, etc., LHRH antagonists such as degarelix, relugolix, etc., abiraterone acetate (Zytiga®), ketoconazole, antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, etc., and other androgen suppressing agents such as estrogens, diethylstilbestrol, etc.

[0051] The term "line 2+" refers to patients with mCRPC who have already received at least two different therapies for the treatment of prostate cancer prior to administration of niraparib: a taxane-based chemotherapy and an androgen receptor (AR) targeted therapy. The term also includes patients with mCRPC who have received a second, third, fourth, or fifth line of therapy prior to administration of niraparib.

[0052] The term "objective response rate" or "ORR" refers to the proportion of subjects or patients (both terms "subject" and "patient" are used interchangeably) with BRCA DNA repair abnormalities and measurable disease, whose best response was either a complete or partial response as defined by RECIST 1.1 (Eisenhauer et al., 2009), and no evidence of bone progression according to PCWG3 criteria (Scher et al., 2016).

[0053] The term "Objective response rate in Non-BRCA Analysis Set" means the objective response rate of soft tissue (visceral or nodal disease) as defined by RECIST 1.1 with no evidence of bone progression according to PCWG3 criteria in subjects with measurable mCRPC and DNA repair defects in ATM FANCA, PALB2, CHEK2, BRIP1, or HDAC2.

[0054] The term "CTC response rate" refers to the proportion of subjects with baseline CTC>0, with CTC=0 per 7.5 mL of blood 8 weeks after baseline.

[0055] The term "Overall Survival" or "OS" refers to the time from enrollment to the date of death from any cause. Subjects who are alive at the time of analysis are censored on the last date that the subject was known to be alive.

[0056] The term "radiographic progression" is determined by the first occurrence of progression as assessed by the investigator.Radiographic progression and bone progression were assessed according to RECIST 1.1 for soft tissue disease and PCWG3 for bone disease as follows: -Progression of soft tissue disease as measured by CT or MRI as defined by RECIST 1.1. Progression due to bone disease as observed by bone scan and based on PCWG 3. Bone progression was defined as one of the following depending on what was observed on the 8-week scan and on the confirmatory scan (performed ≥6 weeks later): 1) Subjects who were observed to have ≥2 new bone lesions at the week 8 scan compared to the baseline scan were classified into one of the following two categories: a) Subjects were considered to have bone scan progression at week 8 if their confirmatory scan showed ≥2 new lesions compared to the week 8 scan (i.e., a total of ≥4 new lesions compared to the baseline scan). b) Subjects whose confirmatory scan did not show ≥2 new lesions compared to the week 8 scan were not considered to have bone scan progression. The week 8 scan was considered the bone scan to which subsequent scans were compared. The first scan time point that showed ≥2 new lesions compared to the week 8 scan was considered the bone scan progression time point if these new lesions were confirmed by a subsequent scan ≥6 weeks later. 2) For subjects whose week 8 scan did not have ≥2 new bone lesions compared to the baseline scan, the first scan time point that showed ≥2 new lesions compared to the week 8 scan was considered the bone scan progression time point if these new lesions were confirmed by a subsequent scan ≥6 weeks later.

[0057] Subjects without radiological progression or death will be censored at the date of last disease assessment if they have not started subsequent anticancer therapy. Subjects who have started subsequent anticancer therapy will be censored at the date of last assessment before starting new anticancer therapy.

[0058] The term "Progression-Free Survival" or "PFS" means the time from treatment enrollment to investigator-assessed disease progression (PSA, radiological (rPFS), symptomatic, or a combination thereof) during anticancer treatment or death (from any cause) before the start of subsequent anticancer treatment, whichever occurs first.

[0059] The term "time to radiographic progression" means the time from enrollment to radiographic progression due to disease progression (as determined by the investigator).

[0060] The term "time to PSA progression" means the time from enrollment to the first date of documented PSA progression based on PCWG3 criteria. Subjects without PSA progression at the time of analysis are censored at the last known date of progression freedom. Subjects without baseline PSA or post-baseline values ​​are censored at the date of enrollment.

[0061] The term "time to symptomatic skeletal event" or "time to SSE" means the time from enrollment to the first occurrence of one of the following symptomatic skeletal related events: i) tumor-related spinal cord compression, ii) radiation to bone to relieve bone-related symptoms, iii) need for surgery or tumor-related orthopedic intervention to bone, iv) symptomatic fracture or pathology. Subjects without symptomatic skeletal related events at the time of analysis are censored at the date of last treatment + 30 days. Death is not considered an SSE event.

[0062] The term "duration of objective response" means the time from complete or partial response to radiological progression of disease, overt clinical progression, or death, whichever occurs first.

[0063] The term "circulating tumor cell (CTC) response rate" refers to the proportion of subjects with baseline CTC>0, with CTC=0 per 7.5 mL of blood 8 weeks after baseline.

[0064] Castration-resistant prostate cancer Agents that block the action of endogenous hormones (e.g., testosterone) (antiandrogens) are highly effective and are routinely used to treat prostate cancer (androgen deprivation therapy). Although these androgen deprivation therapies are initially effective in suppressing tumor growth, they eventually become ineffective in almost all cases, leading to CRPC. Most, but not all, prostate cancer cells initially respond to androgen deprivation therapy, such as bicalutamide, but this response is much less in patients treated with novel hormonal agents. However, over time, a surviving population of prostate cancer cells develops as the prostate cancer cells have become resistant to the selective pressure created by androgen deprivation therapy and are no longer responsive to the treatment. Not only is the primary cancer no longer responsive to the therapy used, but cancer cells can break away from the primary tumor and travel in the bloodstream, metastasizing the disease to distant sites, especially bone. This is known as metastatic castration-resistant prostate cancer ("mCRPC"). Among other effects, this causes the patient significant pain and even bone fragility.

[0065] DNA repair genes Subjects or patients who would benefit from improved treatment of line 2+ mCRPC are human males over 18 years of age who have biallelic abnormalities, also called "biallelic DNA repair abnormalities", in their DNA repair genes. These abnormalities may be somatic or germline. These DNA repair genes include BRCA1 (breast cancer gene 1), BRCA2 (breast cancer gene 2), ATM (ataxia telangiectasia mutated), FANCA (Fanconi anemia complementation group A gene), PALB2 (partner and localizer of BRCA2 gene), CHEK2 (checkpoint kinase 2 gene), BRIP1 (BRCA1 interacting protein C-terminal helicase 1 gene), and HDAC2 (histone deacetylase 2).

[0066] Niraparib Niraparib, or 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide, is an orally available, highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymers. The preparation of niraparib is described in U.S. Patent Nos. 8,071,623 and 8,436,185, both of which are incorporated herein by reference.

[0067] As used herein, the term “niraparib” refers to either the free base compound (2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), salt forms, including pharma- ceutically acceptable salts of 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), and / or solvated forms, including hydrated forms thereof (e.g., 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide tosylate monohydrate). Such forms may be individually referred to as "niraparib free base", "niraparib tosylate" and "niraparib tosylate monohydrate", respectively. Unless otherwise stated, the term "niraparib" includes all crystals, polymorphs, pseudopolymorphs, hydrates, monohydrates, anhydrous forms, solvates, salt forms, and combinations thereof of the compound 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide, as applicable. Examples of salts include, but are not limited to, tosylate or 4-methylbenzenesulfonate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, and lauryl sulfate. In certain embodiments, the term "niraparib" refers to niraparib tosylate monohydrate.

[0068] The term "niraparib" also encompasses amorphous and crystalline polymorphs of the compound, as well as hydrates, unsolvates, and solvates thereof. Examples of polymorphs are described in WO 2018 / 183354(A1), which is incorporated herein by reference. Crystalline Form I of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide tosylate monohydrate is characterized by at least one X-ray diffraction pattern reflection selected from 2θ values ​​of 9.5±0.2, 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 24.9±0.2, 25.6±0.2, 26.0±0.2, and 26.9±0.2. The crystalline form II of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide tosylate non-stoichiometric hydrate is characterized by at least one X-ray diffraction pattern reflection selected from 9.7±0.3, 12.8±0.3, 17.9±0.3, 19.7±0.3, and 21.8±0.3 2θ values. The crystalline form III of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide tosylate anhydrous form is characterized by at least one X-ray diffraction pattern reflection selected from 17.8±0.2, 19.0±0.2, or 22.8±0.2 2θ values. The crystalline form I is preferred. Further examples of polymorphs are described in WO 2020 / 072797(A1), which is incorporated herein by reference.

[0069] The term "niraparib eq." or "niraparib equivalent" refers to the free base dose of niraparib.

[0070] The present invention also provides a pharmaceutical composition comprising niraparib and a pharma- ceutical acceptable carrier. The pharmaceutical composition comprising the active ingredient may be in a form suitable for oral use, such as, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0071] Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a medicament of pharma- ceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone, or acacia; and lubricating agents, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to mask unpleasant tastes of the drugs or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.

[0072] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier, for example, polyethylene glycol, or an oil medium such as, for example, peanut oil, liquid paraffin, or olive oil.

[0073] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents may be, for example, naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearates), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanal), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g. polyoxyethylene sorbitol monooleates), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyethylene sorbitan monooleates). The aqueous suspensions may also contain one or more preservatives, such as, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or aspartame.

[0074] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents, such as those mentioned above, may be added to obtain a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as butylated hydroxyanisole or alpha-tocopherol.

[0075] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Further excipients, such as sweeteners, flavorings, and colorings, may also be present.These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0076] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phosphatides (e.g., soybean lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of said partial esters with ethylene oxide (e.g., polyoxyethylenesorbitan monooleate). The emulsion may further contain sweeteners, flavorings, preservatives, and antioxidants.

[0077] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may further contain demulcents, preservatives, flavoring and coloring agents, and antioxidants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution.

[0078] The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. This oily solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion.

[0079] The injectable solution or microemulsion may be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a manner that a constant circulating concentration of the compound is maintained. To maintain such a constant concentration, a continuous intravenous delivery device may be utilized. One example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

[0080] The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension or a sterile injectable oleaginous suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. It should be noted that fatty acids such as oleic acid can be used in the preparation of injectable preparations.

[0081] Niraparib may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperatures and therefore melts in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of different molecular weights and fatty acid esters of polyethylene glycol.

[0082] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound are employed. (For purposes of this application, topical application includes mouthwashes and gargles.)

[0083] Niraparib can be administered in intranasal form by topical use of suitable intranasal solutions and delivery devices, or by transdermal routes using transdermal patch forms well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the dosage will, of course, be continuous rather than intermittent throughout the entire administration regimen. Niraparib may also be delivered as a suppository using a base such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oil, a mixture of polyethylene glycols of different molecular weights and fatty acid esters of polyethylene glycol. EXAMPLES

[0084] These examples are presented for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0085] Example 1: A two-phase efficacy and safety study of niraparib in men with metastatic castration-resistant prostate cancer and DNA repair defects - the Galahad study Study Centers: Participants were enrolled across 15 countries: Australia (8 sites), Belgium (9 sites), Brazil (8 sites), Canada (5 sites), Denmark (1 site), France (9 sites), Israel (4 sites), Netherlands (4 sites), South Korea (3 sites), Russia (3 sites), Spain (10 sites), Sweden (4 sites), Taiwan (4 sites), UK (7 sites), and US (14 sites).

[0086] the purpose:

[0087] [Table 2]

[0088] Methodology: This was a two-stage, multicenter, open-label clinical trial to evaluate the efficacy and safety of niraparib 300 mg once daily in male subjects aged 18 years and older with mCRPC and DNA repair defects who had received prior taxane-based chemotherapy and AR-targeted therapy. The planned sample size was approximately 120 subjects with biomarker-positive measurable disease (approximately 75 subjects with DNA repair defects in BRCA [BRCA1 or BRCA2] and approximately 45 subjects with biallelic DNA repair defects in non-BRCA [ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2]).

[0089] In addition, at least 90 subjects with non-measurable disease (i.e., bone disease only), regardless of DNA abnormality (i.e., BRCA or non-BRCA), were included to evaluate the activity of niraparib in this population. Efficacy objectives were evaluated for subjects who met the biomarker inclusion criteria described in the protocol. All subjects were monitored for safety throughout the study and until 30 days after the last dose of study drug. Treatment continued until disease progression, unacceptable toxicity, death, or termination of the study by the sponsor.

[0090] Study population Number of Subjects (Planned and Analyzed): Enrollment of 120 biomarker-positive subjects with measurable disease was planned for the study, with at least 90 subjects with non-measurable disease (i.e., bone disease only) included as well.

[0091] In this analysis, a total of 289 subjects who enrolled in the study and received at least one dose of niraparib were included in the safety population. The biallelic / germline population used for efficacy analysis consisted of 223 subjects with biallelic DRD loss. Of the 223 subjects, 142 had BRCA DRD and 81 had non-BRCA DRD.

[0092] Main criteria for diagnosis and inclusion: The target population consisted of male subjects aged >18 years with mCRPC and DNA repair defects (biallelic and germline pathogenic mutations for BRCA1 or BRCA2 mutations only) who had received at least one prior taxane-based chemotherapy and at least one prior AR-targeted therapy (second generation or later). Subjects were asked to provide tumor tissue samples (archived or recently collected, if available) and blood samples for analysis of DNA repair defects using sponsor-certified assays.

[0093] Subjects must have demonstrated evidence of disease progression during or after treatment with taxane-based chemotherapy and a second-generation AR-targeted therapy for metastatic prostate cancer, or have discontinued taxane-based chemotherapy due to an AE.

[0094] In the setting of castrate levels of testosterone in subjects receiving GnRHa or due to bilateral orchiectomy, progression of metastatic prostate cancer had to be documented by PSA progression, or soft tissue radiological progression by RECIST 1.1, or bone disease by PCWG3 criteria.

[0095] Subjects, if not surgically castrated, were required to continue gonadotropin releasing hormone analogs during the course of the study.

[0096] Preliminary Screening Eligibility Criteria ● A signed Preliminary Screening ICF. Willingness to provide tumor tissue samples (archived or recently collected) and blood samples for analysis of DNA repair abnormalities using sponsor-validated assays. Must have received or have received at least one taxane-based chemotherapy and at least one AR-targeted (second generation or later) therapy for metastatic prostate cancer.

[0097] Inclusion criteria Subjects enrolled in the study were required to meet the following important inclusion criteria: • Histologically confirmed prostate cancer (mixed histology was acceptable except for small cell pure phenotype, which was excluded). Have received taxane-based chemotherapy for the treatment of metastatic prostate cancer with evidence of disease progression during or after treatment, or have discontinued taxane-based chemotherapy due to adverse events. Have received second-generation or later AR-targeted therapy (e.g., abiraterone acetate + prednisone, enzalutamide, apalutamide) for the treatment of metastatic prostate cancer with evidence of disease progression and non-mCRPC with evidence of subsequent metastasis. Biomarker positivity according to at least one of the following criteria: Biallelic DNA repair defects based on sponsor-certified blood or tissue assays. Germline pathogenic BRCA1 or BRCA2 by any test (somatic local result must be confirmed as positive by a sponsor-validated assay prior to dosing). Progression of metastatic prostate cancer in the setting of castrate levels of testosterone ≤ 50 ng / dL on GnRHa or history of bilateral orchiectomy at study entry as defined by the protocol. If not surgically castrated, GnRHa may be continued during the course of the study.

[0098] Exclusion criteria Subjects were not enrolled in the study if, during pretesting, they met any of the following key criteria: • Prior treatment with a PARP inhibitor. • Upfront platinum-based chemotherapy for the treatment of prostate cancer. • Known history or current diagnosis of MDS / AML. Symptomatic or impending spinal cord compression, unless the subject has received definitive treatment for this and shows evidence of clinically stable disease. • Symptomatic brain metastases. - Known allergy, hypersensitivity, or intolerance to niraparib or any of its excipients.

[0099] [Table 3]

[0100] [Table 4]

[0101] Dosage and Administration Study product, dose, and mode of administration: Subjects received 300 mg of niraparib as 3 x 100 mg capsules for oral administration once daily.

[0102] Treatment duration: Treatment began on day 1 of cycle 1 of the treatment phase and continued in 28-day cycles until study drug was discontinued.

[0103] [Table 5]

[0104] Test evaluation Evaluation criteria: Efficacy assessments included chest, abdominal, and pelvic CT or MRI scans and whole body bone scans ( 99m Tc). Serum PSA, CTC, vital status, and SSE were also collected. PROs included BPI-SF, FACT-P, and EQ-5D-5L questionnaires. Safety assessments included recording of AEs, physical examination, vital signs, ECG, and ECOG performance status. Clinical laboratory tests included hematology, blood chemistry, and liver function parameters. Blood samples were also collected for pharmacokinetic evaluation and biomarker analysis. Archival or recent tumor tissue samples were obtained from subjects who consented for biomarker identification.

[0105] Statistical methods: Efficacy analyses were performed on the ITT population, which included subjects who received at least one dose of study drug and had BRCA (biallelic or germline DNA repair deficiency) or non-BRCA (biallelic DNA repair deficiency). The primary endpoint was ORR, which was summarized for the BRCA analyzed population with 95% two-sided exact CI. The number and percentage of subjects in each response category (CR, PR, etc.) were tabulated. ORR in non-BRCA subjects was analyzed in the same manner.

[0106] A narrative summary of CTC response was generated for the BRCA and non-BRCA analysis subject populations, measurable and non-measurable subgroups, and tabulated with their two-sided 95% exact CIs. Waterfall plots of the percent change in CTCs were also presented, showing the percent change in CTC count from baseline to week 8, as well as the maximum CTC count reduction. The secondary endpoint of overall time to event was evaluated for the BRCA and non-BRCA analysis subject populations using the Kaplan-Meier method. Median time to event and corresponding 95% CIs were provided. A narrative summary was provided for the BRCA and non-BRCA analysis subject populations. Additionally, waterfall plots for PSA were presented to demonstrate the percentage change in PSA from baseline to week 12 (or earlier for those who discontinued treatment), as well as the maximum PSA decline.

[0107] Descriptive statistics (N, mean, standard deviation, median, observed minimum, maximum, and change from baseline) were provided for each component of the BPI-SF, FACT-P, and EQ-5D-5L. Time to resolution was determined using the following significant change thresholds: FACT-P total (10-point decrease from baseline), EQ-5D-5L index (0.09-point decrease from baseline), EQ-5D-5L VAS (10-point decrease from baseline), and BPI SF worst pain intensity item (30% decrease from baseline).

[0108] All AEs reported from the date of first dose through 30 days (inclusive) after the last dose of study drug were considered treatment-emergent and summarized. AE incidence was summarized as frequency and percentage by SOC and preferred period, with all subjects as the denominator, unless otherwise stated. AE incidence was also summarized by severity and relationship to study drug. Treatment-related AEs were those judged by the investigator to be at least probably related to the study drug. Subjects with multiple occurrences of an event were counted only once at the maximum severity for the study drug for each preferred team, SOC, and overall. Deaths occurring within 30 days after the last dose of study drug were defined as on-study deaths. No inferential statistical analyses were performed when analyzing safety data.

[0109] Primary Endpoint The primary endpoint was ORR, defined as the proportion of subjects with BRCA DNA repair abnormalities and measurable disease whose best response was either CR or PR as defined by RECIST 1.1 (Eisenhauer et al., 2009) and no evidence of bone progression according to PCWG3 criteria (Scher et al., 2016).

[0110] The primary estimate, which was the primary clinical quantity of interest estimated in this study, was defined by the following four components: Population: All subjects with measurable disease in the BRCA analysis population Variable: ORR based on investigator assessment Concomitant events and guidelines:

[0111] [Table 6] Population-level summary: ORRs were summarized for the BRCA analysis population with 95% two-sided exact CIs.

[0112] The final ORR analysis was performed for the last subject with a BRCA DNA repair defect and measurable disease approximately 6 months after day 1 of cycle 1. Objective response as determined by investigator assessment was considered the primary analysis.

[0113] Additionally, all enrolled subjects with non-BRCA DNA repair defects and measurable disease as defined by RECIST 1.1 (Eisenhauer et al., 2009) were analyzed for objective response.

[0114] Subjects who discontinued the study without response assessment were considered non-responders in the analysis. Objective response rates were calculated and presented with two-sided 95% exact CIs. The number and percentage of subjects in each response category (CR, PR, etc.) are summarized in the table.

[0115] Secondary Endpoints Secondary endpoints included ORR in the non-BRCA analyzed population, CTC response rate, OS, rPFS, time to radiological progression, time to PSA progression, time to SSE, and duration of objective response.

[0116] Secondary Endpoint Analyses: ORR in BRCA and non-BRCA subjects was analyzed in the same manner.

[0117] The following analyses of CTC response were performed for the BRCA and non-BRCA analyzed subject populations, measurable and non-measurable subgroups. -Descriptive Overview CTC response rates were tabulated with their two-sided 95% exact CIs.

[0118] Waterfall plots of the percent change in CTCs were also presented, showing the percent change in CTC counts from baseline to week 8, as well as the maximum CTC count reduction.

[0119] The secondary endpoint of overall time to event was assessed using the Kaplan-Meier method for BRCA and non-BRCA analyzed subject populations. Median time to event and corresponding 95% CI were provided. A narrative summary was provided for BRCA and non-BRCA analyzed subject populations. Additionally, waterfall plots for PSA were presented to demonstrate the percentage change in PSA from baseline to week 12 (or earlier for those who discontinued treatment), as well as the maximum decline in PSA.

[0120] result Study population All 289 subjects (100%) enrolled in the study were treated with 300 mg niraparib and were included in the safety population. The median follow-up was 10 months (range 0.3-47 months) in the enrolled analysis population. At the time of clinical data cut-off (January 26, 2021), 94% of subjects prematurely discontinued niraparib treatment. The most common reason for treatment discontinuation was progressive disease (71%), followed by adverse events (14%). After treatment discontinuation, subjects continued on study for survival, disease assessment, and SSE. At the time of analysis, 6% of subjects were still on study (including subjects who entered the long-term extension), and 94% of subjects prematurely terminated study participation. Death was the primary reason for early study discontinuation (72% of subjects).

[0121] The majority of subjects were white (70%), with a median age of 69 years (range 46-88 years). Subjects in the primary efficacy analysis population (measurable BRCA ITT) were slightly younger, with a median age of 66 years (range 47-86 years). Demographics of the enrolled BRCA ITT and non-BRCA ITT populations were comparable to the ITT population.

[0122] All subjects had evidence of disease progression at study entry. 74% of subjects had both PSA and radiological progression at entry. Most subjects had an ECOG performance status score of either 0 (30%) or 1 (56%) at baseline. The majority of subjects (69%) had a Gleason score of 8 or higher. Nearly all subjects (92%) had bone metastases, and 24% of subjects had visceral disease, primarily caused by liver metastases. The incidence of visceral disease was even higher in subjects with measurable disease and BRCA DRD (30 of 76 subjects [40%]). All other baseline disease characteristics were comparable across the analysis population.

[0123] result ●Treatment with 300 mg of niraparib resulted in an ORR of 34.2% (95% CI: 23.7-46.0) in BRCA subjects with measurable disease. Complete responses were observed in two BRCA subjects with measurable disease; in one subject, the response was maintained for 9.7 months, and in the other, the response lasted a total of 9.5 months. The CTC response rate was 24% in BRCA subjects and 18% in the combined group, compared with a rate of 9% in non-BRCA subjects. Median OS was 12 months in the total ITT population with 153 events (69% of ITT subjects). More favorable survival was observed in BRCA subjects (13 months) compared with non-BRCA subjects (10 months). Median rPFS was 5.6 months in the overall ITT population, with 144 events occurring in 65% of subjects. In 142 BRCA subjects, median rPFS was longer at 8.1 months, with 87 events occurring in 61% of BRCA subjects. The time to radiographic progression was 5.8 months in the ITT population, with 134 events occurring in 60% of patients. The time to radiographic progression was slightly longer in BRCA patients, with 81 events in 57% of BRCA patients. Median time to PSA progression was reached at 4.6 months in the ITT population (124 events, 56% of subjects) and was similar in BRCA subjects (85 events, 60% of subjects). Sixty-five events in 29% of subjects were recorded in the ITT population. The incidence of symptomatic skeletal-related events was similar in BRCA subjects, with 46 events in 32% of subjects. The median time to symptomatic skeletal-related events was approximately 13 months in the overall ITT and BRCA ITT populations. Among 31 subjects with measurable disease who responded to niraparib treatment, the median duration of objective response was 5.55 months (range: 3.91-7.20). Response duration was similar regardless of gene mutation status. Adherence to PRO assessments was high. FACT-P, and EQ-5D-5L VAS and index scores appeared stable over time and similar between groups.

[0124] [Table 7]

[0125] [Table 8]

[0126] [Table 9]

[0127] [Table 10]

[0128] [Table 11]

[0129] [Table 12]

[0130] [Table 13]

[0131] [Table 14]

[0132] [Table 15]

[0133] [Table 16]

[0134] Safety Results All but one subject experienced at least one AE (99.7%), and 90% of subjects reported a related AE. SAEs were reported by 46.4% of subjects. AEs led to treatment discontinuation in 22.8% of subjects. One subject reported an AE related to COVID-19, which was not considered serious. One death due to COVID-19 occurred, but this occurred outside the reporting period for treatment-emergent AEs. Grade 3 or 4 AEs occurred in 75.1% of subjects. The most common were anemia (32.9%), thrombocytopenia (16.3%), and neutropenia (9.7%), fatigue (6.6%), and nausea (5.2%). The most common grade 4 AE was thrombocytopenia in 23 (8.0%) subjects. As of the data cutoff date, 26 (9%) subjects had died within 30 days of their last dose of study drug. The majority of these deaths were due to progressive disease (17 [6%] subjects). Deaths due to treatment-emergent AEs occurred in 16 (5.5%) subjects. Clinically significant adverse events (all grades) were as follows: anemia (54.0%), thrombocytopenia (34.3%), neutropenia (19.4%), febrile neutropenia (1.0%) and neutropenic sepsis (0.3%). The most common (≥2.5%) grade 3 or grade 4 clinical chemistry values ​​reported during the study were increased GGT (5.0%), increased alkaline phosphatase and hyperkalemia (2.5% each), and hyponatremia (3.2%). The most common (≥10% of subjects) Grade 3 or Grade 4 hematological values ​​reported were decreased lymphocyte count (18.4% of subjects) and anemia (17.0% of subjects).

[0135] conclusion As of the clinical cutoff date of January 26, 2021, the median follow-up for the primary efficacy population (measurable BRCA) was 10.0 months. Their median age was 66 years, and 57.9% had an ECOG performance status of 1 and 9.2% had an ECOG performance status of 2 at study entry. Most subjects had significant disease burden at baseline, 80% had bone disease, and importantly 40% had visceral disease. Fifty-one subjects (67.1%) received one AR-targeted therapy, of which 37 received one taxane-based chemotherapy, and 14 received two taxane-based chemotherapy. Twenty-five subjects (32.9%) received two AR-targeted therapies, of which 14 received one taxane-based chemotherapy, and 11 received two taxane-based chemotherapy. Most subjects received at least one taxane-based chemotherapy in the mCRPC setting.

[0136] The starting dose of niraparib monotherapy was 300 mg orally daily. The median treatment duration was estimated to be 6.47 months in the BRCA group (N=142) and 3.55 months in the non-BRCA group (N=81).

[0137] GALAHAD was the first study to evaluate niraparib in metastatic prostate cancer and utilized multiple assays to enrich patients with DRD in two cohorts (BRCA and non-BRCA). Treatment with niraparib resulted in an ORR of 34.2% in BRCA subjects in a more heavily pretreated population with more advanced disease stage compared to other studies of PARP inhibitors in mCRPC patients after at least second-line treatment. This finding is noteworthy in a patient population with few remaining treatment options at baseline and a high prevalence of visceral metastases (nearly 40% of patients). Radiographic progression-free survival and overall survival also tended to be longer in the BRCA cohort, with median rPFS being approximately twice that in the non-BRCA cohort.

[0138] The safety profile of niraparib in this heavily pretreated prostate cancer population was manageable. For example, patients received transfusions or erythropoietin to treat anemia and maintain blood counts. The adverse events observed were consistent with the known safety profile of niraparib. Subjects in the primary efficacy population who achieved an objective response had higher relative dose intensity and fewer interruptions compared to non-responders.

[0139] Taken together, these results extend the evidence for the efficacy of PARP inhibitors in mCRPC patients with DRD and those with disease progression on prior therapy, as well as further support the observation that precision medicine may offer significant benefit in this setting, particularly in patients with BRCA1 / 2 mutations.

Claims

1. A pharmaceutical composition for use in a method for improving median overall survival (OS) of approximately 12 months with a 95% confidence interval (CI) in human males with line 2+ metastatic castration-resistant prostate cancer (mCRPC) with biallelic DNA repair defects, comprising: the pharmaceutical composition comprises niraparib; the method comprises administering to the male human a once-daily oral dose of 300 mg of niraparib; The pharmaceutical composition, wherein the biallelic DNA repair defect is selected from i) BRCA1, BRCA2, or a combination thereof, ii) ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof, or iii) any combination thereof, and the male human has previously received taxane-based chemotherapy and androgen receptor (AR)-targeted therapy.

2. 2. The pharmaceutical composition of claim 1, wherein the human male has a BRCA DNA repair defect and the median OS is about 13 months (95% CI).

3. 2. The pharmaceutical composition of claim 1, wherein the human male has a DNA repair defect selected from ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof, and the median OS is about 10 months (95% CI).

4. 2. The pharmaceutical composition of claim 1, wherein the improved efficacy is a median radiographic progression-free survival (rPFS) of about 5.6 months (95% CI).

5. 5. The pharmaceutical composition of claim 4, wherein the human male has a BRCA DNA repair defect and the rPFS is about 8.1 months (95% CI).

6. 2. The pharmaceutical composition of claim 1, wherein the human male has a BRCA DNA repair defect and the improved efficacy is an objective response rate (ORR) of about 34.2% (95% CI).

7. 2. The pharmaceutical composition of claim 1, wherein the improved efficacy is a median duration of objective response of about 5.55 months (95% CI).

8. The pharmaceutical composition according to claim 1, wherein the improved effectiveness is the time (median) to radiographic progression of about 5.8 months (95% CI).

9. The pharmaceutical composition according to claim 8, wherein the human male has a BRCA DNA repair abnormality and the time (median) to radiographic progression is about 8.08 months (95% CI).

10. The pharmaceutical composition according to claim 1, wherein the improved effectiveness is the median time to PSA progression of about 4.6 months (95% CI).

11. The pharmaceutical composition according to claim 1, wherein the improved effectiveness is the median time to symptomatic bone-related events of about 13 months (95% CI).

12. The pharmaceutical composition according to claim 1, wherein the improved effectiveness is a circulating tumor cell (CTC) response rate of about 18% (95% CI).

13. The pharmaceutical composition according to claim 12, wherein the human male has a BRCA DNA repair abnormality and the CTC response rate is about 24% (95% CI).

14. The pharmaceutical composition according to claim 12, wherein the human male has a DNA repair abnormality selected from ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof, and the CTC response rate is about 9% (95% CI).

15. The pharmaceutical composition according to claim 1, wherein the taxane-based chemotherapy is docetaxel, paclitaxel, or cabazitaxel.

16. The AR targeted therapy is i) surgical castration (orchiectomy), or ii) medical castration selected from the group consisting of luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprorelin or leuprolide, goserelin, triptorelin, histrelin, nafarelin, gonadorelin, buserelin, etc., LHRH antagonists such as degarelix, relugolix, etc., abiraterone acetate (Zytiga (registered trademark)), ketoconazole, antiandrogens, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, etc., and other androgen-suppressing agents, such as estrogen, diethylstilbestrol, etc., the pharmaceutical composition according to claim 1.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein niraparib is in the form of a salt of tosylate monohydrate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate.

18. 1. Use of niraparib for the manufacture of a pharmaceutical composition for use in a method of improving median overall survival (OS) of approximately 12 months with a 95% confidence interval (CI) in male human beings with line 2+ metastatic castration-resistant prostate cancer (mCRPC) harboring biallelic DNA repair defects, wherein the biallelic DNA repair defects are selected from: i) BRCA1, BRCA2, or a combination thereof; ii) ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof; or iii) any combination thereof; the male human being has received prior taxane-based chemotherapy and androgen receptor (AR)-targeted therapy; and the method comprises administering to the male human a once-daily oral dose of 300 mg of niraparib.

19. 19. The use of claim 18, wherein the human male has a BRCA DNA repair defect and the median OS is about 13 months (95% CI).

20. 19. The use of claim 18, wherein the human male has a DNA repair defect selected from ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof, and the median OS is about 10 months (95% CI).

21. 19. The use of claim 18, wherein the improved efficacy is a median radiological progression-free survival (rPFS) of about 5.6 months (95% CI).

22. 22. The use of claim 21, wherein the human male has a BRCA DNA repair defect and the rPFS is about 8.1 months (95% CI).

23. 19. The use of claim 18, wherein the human male has a BRCA DNA repair defect and the improved efficacy is an objective response rate (ORR) of about 34.2% (95% CI).

24. 19. The use of claim 18, wherein the improved efficacy is a median duration of objective response of about 5.55 months (95% CI).

25. 19. The use of claim 18, wherein the improved efficacy is a time to radiological progression of about 5.8 months (95% CI).

26. 26. The use of claim 25, wherein the human male has a BRCA DNA repair defect and the time to radiological progression is about 8.08 months (95% CI).

27. 19. The use of claim 18, wherein the improved efficacy is a median time to PSA progression of about 4.6 months (95% CI).

28. 19. The use of claim 18, wherein the improved efficacy is a median time to symptomatic skeletal-related events of about 13 months (95% CI).

29. 19. The use of claim 18, wherein the improved efficacy is a circulating tumor cell (CTC) response rate of about 18% (95% CI).

30. 30. The use of claim 29, wherein the human male has a BRCA DNA repair defect and the CTC response rate is about 24% (95% CI).

31. 30. The use of claim 29, wherein the human male has a DNA repair defect selected from ATM, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or any combination thereof, and the CTC response rate is about 9% (95% CI).

32. 19. The use of claim 18, wherein the taxane chemotherapy is docetaxel, paclitaxel, or cabazitaxel.

33. 19. The use of claim 18, wherein the AR-targeted therapy is i) surgical castration (orchiectomy), or ii) medical castration selected from the group consisting of luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide or leuprolide, goserelin, triptorelin, histrelin, nafarelin, gonadorelin, buserelin, etc., LHRH antagonists, such as degarelix, relugolix, etc., abiraterone acetate (Zytiga®), ketoconazole, antiandrogens, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, etc., and other androgen-suppressing drugs, such as estrogen, diethylstilbestrol, etc.

34. The use according to any one of claims 18 to 33, wherein niraparib is in a salt form of tosylate monohydrate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate.

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