Methods of Treating Prostate Cancer

Abstract

The present disclosure relates to methods of treating prostate cancer in a subject. More specifically, the present disclosure relates to methods of treating prostate cancer, e.g., metastatic castration-resistant prostate cancer, by administering to a subject olaparib and abiraterone acetate or a salt thereof.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating prostate cancer in a subject, more particularly, to methods of treating prostate cancer, e.g., metastatic castration-resistant prostate cancer, by administering olaparib and abiraterone to a subject. [Background technology]

[0002] Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease with poor outcomes. Tumors in up to 30% of patients with mCRPC harbor deleterious DNA damage repair gene abnormalities. Among the most common of these alterations, BRCA1 and BRCA2 are well-characterized homologous recombination repair (HRR) genes, and ATM functions indirectly to detect DNA damage and activate HRR. Loss-of-function alterations in these and other genes with direct or indirect roles in HRR are associated with more aggressive prostate cancer.

[0003] Molecular stratification for treatment is not currently the standard of care for metastatic prostate cancer, despite evidence of substantial interpatient genomic heterogeneity. Most treatment strategies for advanced prostate cancer target androgen receptor signaling; taxane-based chemotherapy and radiopharmaceuticals have also been approved. Although these drugs have improved outcomes over the past decade, metastatic prostate cancer remains invariably fatal, and new treatment strategies, including molecular stratification, are urgently needed.

[0004] Genomic studies of metastatic prostate cancer have identified numerous potentially actionable recurrent genomic abnormalities, including loss-of-function alterations in DNA repair genes, e.g., defects in the HRR gene, in 20-25% of cases. HRR gene alterations confer sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in prostate and other cancers. Antitumor activity has been reported for the PARP inhibitor, olaparib, in patients with mCRPC harboring HRR gene alterations. Response to PARP inhibition may occur via multiple mechanisms, including PARP trapping, physical blockage of replication forks resulting in DNA double-strand breaks, and defects in HRR.

[0005] Current treatment options in the first-line setting for mCRPC consist primarily of the next-generation hormonal agents (NHAs) abiraterone and enzalutamide, and taxane-based chemotherapy, depending on the type of treatment the patient received after initial diagnosis. Despite the reported clinical activity of these agents, overall survival is approximately 3 years, with 5-year survival rates of approximately 30%. In real-world settings, approximately 50% of patients with mCRPC receive only one life-prolonging therapy.

[0006] Thus, there remains a need for treatments that provide significant delay in the progression and recurrence of prostate cancer, and potentially improved cure rates. Summary of the Invention [Means for solving the problem]

[0007] One aspect of the present disclosure provides a method for treating prostate cancer in a subject.Such method includes administering to the subject a therapeutically effective amount of 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or its salt, hydrate, solvate or prodrug; and administering to the subject a therapeutically effective amount of (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (abiraterone acetate) or its salt, hydrate or solvate.

[0008] Another aspect of the disclosure provides olaparib, or a salt, hydrate, solvate, or prodrug thereof, for use in treating prostate cancer in a subject, said treatment comprising administration of said olaparib, or a salt, hydrate, solvate, or prodrug thereof, and abiraterone acetate, or a salt, hydrate, or solvate thereof, to said subject.

[0009] In certain embodiments of the methods, uses, and compositions of the disclosure, progression-free survival is at least about 6 months longer for patients receiving olaparib, or a salt, hydrate, solvate, or prodrug thereof, and abiraterone, or a salt, hydrate, or solvate thereof, than subjects receiving abiraterone acetate alone.

[0010] In certain embodiments of the disclosed methods, uses and compositions, the prostate cancer is mCRPC and the subject is treatment naive.

[0011] In certain embodiments of the methods, uses, and compositions of the present disclosure, the subject has not been selected for a homologous recombination repair (HRR) gene mutation in the cancer.

[0012] These and other features and advantages of the present invention will be more fully understood from the following detailed description taken in conjunction with the appended claims, which should be noted that the claims are defined by their references and not by the specific discussion of the features and advantages set forth in this detailed description.

[0013] The accompanying drawings are included to provide a further understanding of the disclosed compositions and methods, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure, and together with the detailed description, serve to explain the principles and operation of the present disclosure. [Brief description of the drawings]

[0014] [Figure 1A] FIG. 1A provides Kaplan-Meier estimates of investigator-assessed imaging-based progression-free survival (PFS) for patients in the study provided in the Examples. [Figure 1B] FIG. 1B provides Kaplan-Meier estimates of imaging-based PFS by blinded independent central review for patients in the study provided in the Examples. [Diagram 2]Figure 2 provides a forest plot of prespecified subgroup analysis of PFS based on imaging by investigator assessment for patients in the study provided in the examples. The analysis performed included the stratification factors selected in the primary pooling policy as covariates. Each subgroup analysis was performed using a Cox proportional hazards model containing terms for treatment, factor, and treatment-factor interaction. A hazard ratio <1 means a lower risk of progression for the group of patients receiving olaparib and abiraterone acetate. The size of the circle is proportional to the number of events. Subgroup categories with less than 5 events in either treatment group have NC listed. *Excludes patients without baseline assessment. ctDNA, circulating tumor DNA; ECOG, Eastern Cooperative Oncology Group; HRRm, homologous recombination repair gene mutation; mHSPC, metastatic hormone-sensitive prostate cancer; NC, non-calculatable; PSA, prostate-specific antigen. [Figure 3A] Figure 3A provides Kaplan-Meier estimates of investigator-assessed overall survival for patients in the study provided in the Examples. In this figure, NR means not reached. [Figure 3B] FIG. 3B provides Kaplan-Meier estimates of time to second progression or death by investigator assessment for patients in the study provided in the Examples. [Figure 3C] Figure 3C provides Kaplan-Meier estimates of time to first post-treatment or death by investigator assessment for patients in the study provided in the Examples. In this figure, NR means not reached. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Before describing the methods and materials of the present disclosure, it should be understood that the aspects described herein are not limited to specific embodiments, and therefore can, of course, vary. It should also be understood that the terms used herein are for the purpose of describing particular aspects only, and are not intended to be limiting, unless specifically defined herein.

[0016] In accordance with the present disclosure, the methods, uses and compositions described herein can be adapted by those skilled in the art to meet desired needs. The present disclosure provides an improvement in the treatment of prostate cancer. In some embodiments, the cancer is prostate cancer that has metastasized. For example, the metastasis is to bone and / or lymph nodes. The metastasis can also be visceral. In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC). The "metastatic" state is defined as at least one metastatic lesion on either bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scan.

[0017] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including mammals, most preferably humans.

[0018] As mentioned above, the disclosed methods, uses and compositions described herein require the administration of olaparib. As used herein, "olaparib" refers to the molecule 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one. The molecule olaparib may be used in the form of its salt, hydrate, solvate, or prodrug. 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib), having the following structure, is disclosed in WO 2004 / 080976 A1, which is incorporated herein by reference. [ka]

[0019] Olaparib is preferably administered in the form of a pharmaceutical composition. The therapeutically effective amount of Olaparib has already been established. For example, in one embodiment, the therapeutically effective amount of Olaparib is in the range of about 400 to 800 mg per day. For example, in one embodiment, Olaparib is administered in an amount of about 600 mg per day (e.g., about 300 mg taken twice a day).

[0020] As used herein, the phrase "therapeutically effective amount" or "effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response desired in a tissue, system, animal, individual or human by a researcher, veterinarian, physician or other clinician.

[0021] The disclosed methods, uses, and compositions described herein also require the administration of abiraterone, or its salts, hydrates, solvates, or prodrugs. One example of a suitable prodrug of abiraterone is abiraterone acetate. As used herein, "abiraterone acetate" refers to the molecule (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (or [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-pyridin-3-yl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate) having the following structure. [ka] The molecule abiraterone acetate may be used as a salt, hydrate or solvate.

[0022] Abiraterone acetate is preferably administered in the form of a pharmaceutical composition. The therapeutically effective dose of abiraterone acetate has already been established. For example, in one embodiment, the therapeutically effective dose of abiraterone is in the range of about 500-1500 mg per day, for example, about 800-1200 mg per day. For example, in one embodiment, abiraterone acetate is administered in an amount of about 1000 mg per day (for example, orally once per day). As already established, abiraterone acetate is given in combination with prednisone (5 mg orally twice per day) or prednisolone (5 mg orally twice per day).

[0023] Administration of olaparib can be asynchronous, sequential, or simultaneous with administration of abiraterone acetate. In certain embodiments, administration is simultaneous and / or sequential.

[0024] The inventors also unexpectedly found that administration of olaparib in combination with abiraterone acetate is sufficient to improve progression-free survival (e.g., imaging-based or radiological progression-free survival, as assessed by Response Evaluation Criteria in Solid Tumors [RECIST 1.1] for soft tissue lesions and / or Prostate Cancer Working Group-3 [PCWG-3] criteria for bone lesions and / or death, "PFS" or "rPFS") in subjects, or other primary treatment indicators, such as overall survival (OS), time to first post-treatment or death (TFST), time to second progression or death (PFS2), objective response rate (ORR), prostate-specific antigen (PSA) response rate, and time to PSA progression, compared to subjects receiving abiraterone acetate alone (i.e., receiving abiraterone acetate without also receiving olaparib). For example, in the overall subject population, the inventors found that progression-free survival was at least about 6 months longer for subjects receiving olaparib in combination with abiraterone acetate than for subjects receiving abiraterone acetate alone. In certain embodiments, progression-free survival is about 6-18 months longer, or about 6-14 months longer, or about 6-12 months longer. In certain embodiments, progression-free survival is about 8-18 months longer, or about 8-14 months longer, or about 8-12 months longer.

[0025] Surprisingly, the improvement in progression-free survival was observed for patients regardless of their HRR gene mutation status (i.e., in both HRRm and non-HRRm subgroups). Thus, in some embodiments, patients are not selected by HRRm. For example, in some embodiments, the method of the present disclosure further comprises selecting the subject based on pretreatment and / or the selection of the patient does not include diagnosing the patient as having cancer cells containing one or more HRR gene mutations. For example, in some embodiments, the method of the present disclosure further comprises selecting the subject without considering the HRRm status of the subject's cancer cells.

[0026] In certain other embodiments of the methods, uses, and compositions of the present disclosure, the prostate cancer is mCRPC that does not contain an HRR gene mutation (e.g., no deleterious or suspected deleterious germline or somatic HRR gene mutations are detected in any sample type by tissue analysis, germline, or plasma test results) (also referred to herein as "non-HRRm").

[0027] Another embodiment of the present disclosure provides the method, use and composition, wherein the prostate cancer is a homologous recombination deficient (HRD) cancer.For example, whether a cancer is HRD positive can be determined by Myriad Genetics' myChoice® HRD, myChoice® HRD Plus, or suitable equivalent assay.In some other embodiments, the method of the present disclosure further comprises identifying the subject as having cancer cells that contain one or more HRR gene mutations.

[0028] In certain other embodiments of the methods, uses, and compositions of the present disclosure, the prostate cancer comprises one or more HRR gene mutations (also referred to herein as "HRRm"). As used herein, HRR gene mutations include deleterious or suspected deleterious germline or somatic mutations detected in one or more of the analyzed samples, including tissue, germline, and plasma.

[0029] In some embodiments, the cancer cells comprise an HRR gene mutation selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L gene mutations. In some embodiments, the cancer cells comprise a BRCA1, BRCA2, and / or ATM gene mutation. In some other embodiments, the methods, uses, and compositions of the disclosure further comprise identifying a subject having cancer cells comprising a BRCA1, BRCA2, and / or ATM gene mutation. In some embodiments, the cancer cells comprise a BRCA1 and / or BRCA2 gene mutation. In some embodiments, the cancer cells comprise an ATM gene mutation. In certain embodiments, the cancer cells comprise a BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and / or RAD54L gene mutation.

[0030] In certain other embodiments of the methods, uses, and compositions of the disclosure, the prostate cancer is mCRPC that contains one or more HRR gene mutations.

[0031] In certain embodiments, where the subject is treatment naive as defined below, progression free survival is about 6 to 18 months longer (e.g., about 6 to 14 months longer, or about 6 to 12 months longer, or about 8 to 18 months longer, or at least about 6 months longer, or at least about 8 months longer).

[0032] Therefore, in some embodiments, the methods, uses and compositions disclosed herein are also useful as first-line treatments where the subject is treatment-naive. A "treatment-naive" subject, as used herein, is a subject who has not previously received or completed any cytotoxic chemotherapy (e.g., first-line platinum and / or taxane-based chemotherapy or docetaxel) and / or new hormonal agent (NHA) chemotherapy (e.g., enzalutamide or abiraterone), or any other systemic treatment (approved drug or experimental compound) for prostate cancer, e.g., mCRPC. In some other embodiments, the treatment-naive subject has previously received docetaxel during the localized prostate cancer treatment stage or for metastatic hormone-sensitive prostate cancer (mHSPC) stage. In some other embodiments, the treatment-naive subject has not previously received abiraterone, or its salt, hydrate, solvate, or ester (e.g., abiraterone acetate) for prostate cancer, e.g., during any treatment stage.

[0033] In certain other embodiments of the methods, uses, and compositions of the present disclosure, the prostate cancer is mCRPC and the subject has not previously received docetaxel.

[0034] In certain embodiments where the subject has received prior chemotherapy (e.g., docetaxel) during neoadjuvant / adjuvant treatment for localized prostate cancer and / or metastatic hormone sensitive (mHSPC) stage disease, progression-free survival is about 8 to 24 months longer (e.g., about 8 to 20 months longer, or about 8 to 18 months longer, or at least about 8 months longer, or at least about 10 months longer, or at least about 12 months longer).

[0035] Therefore, the method, use and composition of the present disclosure are also useful as second-line treatments where the subject has previously undergone first-line treatment.In some embodiments, the method, use and composition of the present disclosure can provide delay in the progression and recurrence of cancer in subjects who have previously undergone or completed first-line chemotherapy.For example, in some embodiments, the subject has previously undergone or completed first-line platinum and / or taxane-based chemotherapy, such as docetaxel.In some other embodiments, the subject has previously undergone or completed NHA chemotherapy, such as enzalutamide or abiraterone.

[0036] In certain other embodiments of the methods, uses, and compositions of the present disclosure, the prostate cancer is mCRPC and the subject has previously received docetaxel. EXAMPLES

[0037] The methods, uses, and compositions of the present disclosure are further illustrated by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described therein.

[0038] Study design and objectives The efficacy of olaparib versus enzalutamide or abiraterone was evaluated in PROfound (NCT02987543), a randomized, open-label, multicenter trial. The PROfound trial demonstrated that imaging-based progression-free survival and overall survival benefited from olaparib in patients with mCRPC harboring BRCA1, BRCA2, and ATM mutations whose disease progressed while taking NHAs. A trend toward improved imaging-based progression-free survival and overall survival was also observed in patients in the overall study population with HRR gene alterations.

[0039] The rationale for this study is based on preclinical models suggesting that when PARP inhibitors are combined with NHA, there may be a combined antitumor effect for patients regardless of whether they have HRR gene mutations (HRRm). Without being bound by theory, this is potentially due to PARP involvement in the positive co-regulation of AR signaling, which leads to improved AR target gene suppression when PARP / androgen receptor (AR) signaling is co-inhibited. Some studies have reported that NHA inhibits the transcription of some HRR genes; thus, it induces HRR deficiency and increased sensitivity to PARP inhibitors through non-genetic mechanisms.

[0040] The study design was carried out as the PROpel study (NCT03732820), a double-blind, randomized Phase III study of abiraterone acetate and olaparib in the first-line treatment of patients with mCRPC, described in this example. Eligible patients were randomized to receive abiraterone acetate and olaparib or abiraterone acetate and placebo. The primary objective was efficacy as assessed by investigator-assessed imaging-based progression-free survival. The claimed embodiments are based on data and observations generated during the PROpel study.

[0041] method Patient population. Eligible patients were ≥18 years old (or ≥19 years old in Korea) and had histologically or cytologically confirmed prostate adenocarcinoma with at least one reported metastatic lesion on either bone scan, computed tomography, or magnetic resonance imaging scan. No prior systemic treatment was permitted in the mCRPC first-line setting (i.e., patients were treatment-naïve at the mCRPC stage, e.g., patients should not have received any cytotoxic chemotherapy, NHA, or other systemic treatment (approved drugs or experimental compounds) in the mCRPC setting), except for androgen deprivation therapy (ADT) and first-generation antiandrogens (e.g., bicalutamide, nilutamide, and flutamide) with a 4-week washout period. Docetaxel during neoadjuvant / adjuvant treatment for localized prostate cancer and metastatic hormone-sensitive (mHSPC) stage was permitted as long as no signs of failure or disease progression occurred during or immediately after such treatment. Treatment with second-generation antiandrogens (except abiraterone) prior to mCRPC stage and without PSA / clinical / radiological progression during treatment was permitted, provided treatment was stopped at least 12 months prior to randomization.

[0042] Study design and interventions. This was a double-blind, placebo-controlled, phase III study. Eligible patients were randomized (1:1) to treatment with abiraterone acetate (1000 mg once daily) in combination with either olaparib (300 mg twice daily) or placebo. All patients received prednisone or prednisolone (5 mg twice daily) according to abiraterone acetate label requirements. Randomization was stratified by distant metastasis type at baseline (bone only / visceral / other) and by docetaxel treatment at mHSPC stage (yes or no). Study treatment continued until objective imaging-based disease progression assessed by the investigator (using Response Evaluation Criteria in Solid Tumors [RECIST 1.1] for soft tissue lesions and Prostate Cancer Working Group-3 [PCWG-3] criteria for bone lesions), unacceptable toxicity, or withdrawal of consent. After objective disease progression, further treatment options were at the discretion of the investigator. Patients could continue on study treatment if the investigator determined they could continue to receive clinical benefit, were not experiencing serious toxicity, and had no better alternative treatments available. Crossover from placebo to receive olaparib in combination with abiraterone acetate was not permitted.

[0043] Endpoints. The primary endpoint was imaging-based progression-free survival or death from any cause in the absence of disease progression. Sensitivity analyses by blinded independent central review and exploratory subgroup analyses of investigator-assessed imaging-based progression-free survival were prespecified to assess the consistency of treatment effects across potential prognostic factors. Subgroups included HRRm status.

[0044] The main secondary endpoint was overall survival. Other secondary endpoints included time to first post-treatment or death (TFST), time to second progression or death (PFS2) and patient-reported outcomes. Further exploratory endpoints were objective response rate (ORR), prostate-specific antigen (PSA) response rate and time to PSA progression.

[0045] Safety was assessed via reporting of adverse events and serious adverse events (according to the Common Terminology Criteria for Adverse Events v.4.03) based on physical examination findings, vital signs, ECG findings, and laboratory findings.

[0046] Statistical Analysis: Efficacy was analyzed for the analysis set, and safety was analyzed for all patients who received any dose of abiraterone acetate, olaparib, or placebo. Patients who received at least one dose of olaparib were included in the abiraterone acetate and olaparib arms.

[0047] The first planned interim analysis of the primary endpoint of imaging-based progression-free survival is reported in this example. Imaging-based progression-free survival will subsequently be reported at the second data cutoff. Overall survival will be formally examined at all time points, including the third data cutoff.

[0048] With a sample size of 796 patients, the first interim analysis was planned to occur when there had been approximately 379 progression or death events (47.6% maturity), providing 94.1% power with a one-sided alpha of 0.014 to demonstrate a statistically significant difference in imaging-based progression-free survival between the study arms, assuming a hazard ratio for progression or death of 0.68.

[0049] The multiple testing procedure controlled for an overall one-sided type I error rate of 2.5%. If the primary endpoint of imaging-based progression-free survival was statistically significant, overall survival was tested hierarchically.

[0050] For time-to-event endpoints, two-sided P values ​​were calculated using the stratified log-rank test. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with the two stratification variables as covariates. Medians were calculated using Kaplan-Meier plots.

[0051] result Screening and Randomization. This multicenter study across 17 countries screened 1103 patients; 796 patients met eligibility criteria and were randomized.

[0052] Patient characteristics. A total of 399 patients were randomized to abiraterone acetate and olaparib, and 397 to abiraterone acetate and placebo. Baseline characteristics were generally well balanced between arms (Table 1). Based on ctDNA testing, 67.3% of patients were in the non-HRRm subgroup.

[0053] [Table 1]

[0054] [Table 2]

[0055] [Table 3]

[0056] Efficacy. Analysis was performed after 394 patients had an imaging-based progression event or died (49.5% maturity, data cutoff July 30, 2021). Investigator-assessed median imaging-based progression-free survival was significantly longer in the abiraterone acetate and olaparib arm than in the abiraterone acetate and placebo arm (24.8 vs. 16.6 months; hazard ratio [HR], 0.66; 95% CI, 0.54 to 0.81; P < 0.001) (Figure 1A). There were 168 progression or death events in the abiraterone acetate and olaparib arm and 226 in the abiraterone acetate and placebo arm. The median (range) duration of follow-up for disease progression in patients with censored data was 19.3 (0.03-30.59) months in the abiraterone acetate and olaparib arm and 19.4 (0.03-30.16) months in the abiraterone acetate and placebo arm.

[0057] A prespecified sensitivity analysis of imaging-based progression-free survival by blinded independent central review was consistent with the results of the primary analysis (median 27.6 vs. 16.4 months; HR, 0.61; 95% CI, 0.49-0.74) (Figure 1B). There were 157 progression or death events in the abiraterone acetate and olaparib arm and 218 in the abiraterone acetate and placebo arm. The median (range) duration of follow-up for disease progression in patients with censored data was 19.3 (0.03-30.59) months in the abiraterone acetate and olaparib arm and 19.2 (0.03-30.16) months in the abiraterone acetate and placebo arm.

[0058] Imaging-based progression-free survival benefit was observed across all prespecified subgroups (Figure 2). A global interaction test comparing the fit of the model without interaction terms to a model with all subgroup interactions included was not significant at the 10% level (P = .41), indicating a consistent treatment effect across subgroups.

[0059] The maturity of overall survival data was 28.6%, but there was a trend toward prolonged overall survival (HR, 0.86; 95% CI, 0.66 to 1.12) (Figure 3A). There were 107 deaths in the abiraterone acetate and olaparib arm and 121 deaths in the abiraterone acetate and placebo arm. The median (range) duration of follow-up for disease progression in patients with censored data was 22.2 (0.03 to 32.56) months in the abiraterone acetate and olaparib arm and 21.8 (0.10 to 30.88) months in the abiraterone acetate and placebo arm.

[0060] TFST (HR 0.74; 95% CI, 0.61 to 0.90) and PFS2 (HR 0.69; 95% CI, 0.51 to 0.94) supported an efficacy benefit beyond initial imaging-based progression (Figures 3B and 3C).

[0061] For TFST, there were 183 patients in the abiraterone acetate and olaparib arm who received first subsequent treatment, and 221 patients in the abiraterone acetate and placebo arm. Time to first subsequent treatment (excluding radiation therapy) was defined as the time from randomization to the start date of the first subsequent anticancer treatment after discontinuation of randomized treatment or death from any cause (whichever occurred first). Any patients who were unknown to have died at the time of analysis and were unknown to have had subsequent treatment were censored at the last known time point at which they did not receive first subsequent treatment.

[0062] For PFS2, there were 70 second progression or death events in the abiraterone acetate and olaparib arm and 94 in the abiraterone acetate and placebo arm. Patients who did not have a second disease progression event or died at the time of analysis, or who had a second progression or died after two or more missed visits, were censored at the latest evaluable assessment at which they were known to be alive and free of a second disease progression.

[0063] Among patients with measurable disease at baseline, the ORR was 58.4% (94 of 161 patients) in the abiraterone acetate and olaparib arm versus 48.1% (77 of 160 patients) in the abiraterone acetate and placebo arm (odds ratio, 1.60; 95% CI, 1.02 to 2.53).

[0064] Confirmed PSA responses were 79.3% in the abiraterone acetate and olaparib arm and 69.2% in the abiraterone acetate and placebo arm. Median time to PSA progression was not reached versus 12.0 months in the abiraterone acetate and olaparib arm and in the abiraterone acetate and placebo arm, respectively (HR 0.55, 95% CI 0.45 to 0.68).

[0065] Patient-reported outcomes: The least-squares mean change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score across all visits was -4.85 in the abiraterone acetate and olaparib arm versus -4.03 in the abiraterone acetate and placebo arm (difference, -0.82; 95% CI, -3.56 to 1.92), suggesting no harm to health-related quality of life (HRQoL) when olaparib was added to abiraterone acetate treatment.

[0066] Safety. At data cutoff, the median total duration of exposure was 17.5 months for olaparib, 15.7 months for placebo, 18.2 months for abiraterone acetate and abiraterone acetate in the olaparib arm, and 15.7 months for abiraterone acetate and abiraterone acetate in the placebo arm.

[0067] The three most common adverse events in the abiraterone acetate and olaparib arm were anemia, nausea, and fatigue. Anemia was the most common grade ≧3 adverse event and occurred in 60 patients (15.1%) in the abiraterone acetate and olaparib arm and 13 patients (3.3%) in the abiraterone acetate and placebo arm.

[0068] Rates of cardiovascular events (myocardial infarction, congestive heart failure, and ischemic stroke) were similar between treatment arms. For further details, see Table 2.

[0069] There were 26 cases of pulmonary embolism in the abiraterone acetate and olaparib arm (6.5% of patients) and 7 cases in the abiraterone acetate and placebo arm (1.8% of patients); one event in the abiraterone acetate and olaparib arm was fatal but was considered unrelated to study treatment (see Addendum for further information). Pulmonary embolism led to interruption of olaparib in 8 (2.0%) patients and abiraterone acetate in 6 (1.5%) patients in the abiraterone acetate and olaparib arm; no events led to treatment discontinuation. Deep vein thrombosis occurred in 7 (1.8%) and 3 (0.8%) patients in the abiraterone acetate and olaparib arm and the abiraterone acetate and placebo arms, respectively.

[0070] No incidence of myelodysplastic syndrome or acute myeloid leukemia was reported. There were 12 reports of new primary cancers in the abiraterone acetate and olaparib arm (3.0% of patients) and 10 reports in the abiraterone acetate and placebo arm (2.5% of patients). Three (0.8%) patients in each arm of the study had pneumonia (one in each arm had interstitial lung disease).

[0071] There were 33 cases of COVID-19 (8.3% of patients) in the abiraterone acetate and olaparib arm of the study and 18 cases (4.5% of patients) in the abiraterone acetate and placebo arm, with the majority of patients unvaccinated and from Brazil, Turkey, and the United States. Grade ≥3 cases occurred in 17 (4.3%) and 8 (2.0%) patients in the abiraterone acetate and olaparib arm and abiraterone acetate and placebo arms, respectively.

[0072] [Table 4]

[0073] [Table 5]

[0074] Consideration At the interim analysis, the study met its primary objective of increasing imaging-based progression-free survival with abiraterone and olaparib compared with abiraterone acetate and placebo in patients undergoing first-line treatment for mCRPC. The delay in imaging-based progression-free survival was clinically relevant (approximately 8-11 months longer than abiraterone acetate and placebo) and is the longest reported to date in this population, exceeding the median overall survival reported in a phase III docetaxel trial.

[0075] The active control arms of abiraterone acetate plus prednisone / prednisolone and placebo performed as expected; in chemotherapy-naive patients with advanced mCRPC, the median radiographic progression-free survival with abiraterone acetate was 16.5 months (Ryan CJ et al. Lancet Oncol 2015;16:152-60). This is comparable to the 16.6 months reported herein, illustrating that the combination of abiraterone acetate and olaparib treatment significantly extended imaging-based progression-free survival beyond the current standard of care.

[0076] There was a clinically meaningful improvement in imaging-based progression-free survival in all prespecified subgroups, including those with and without prior docetaxel treatment at mHSPC stage, type of metastasis at baseline, and HRRm status. A summary of the results is provided in Table 3.

[0077] [Table 6]

[0078] [Table 7]

[0079] [Table 8]

[0080] In a phase II study of the PARP inhibitor veliparib in combination with abiraterone acetate versus abiraterone acetate, no significant differences in efficacy outcomes were found for patients with mCRPC when veliparib was added to abiraterone acetate treatment (Hussain M et al. J Clin Oncol 2018;36:991-9). Data from this study showed an imaging-based progression-free survival benefit in patients not selected by HRRm, supporting a treatment benefit in HRRm and non-HRRm subgroups.

[0081] Retrospective analysis demonstrated a strong correlation between PFS2 and overall survival, supporting the use of PFS2 to measure long-term clinical benefit when overall survival cannot be assessed. Although our overall survival data was 28.6% mature, there was a trend toward improved overall survival for olaparib and abiraterone acetate, and the PFS2 results supported long-term improved efficacy outcomes. Kaplan-Meier curves for both endpoints showed similar patterns, with separation occurring earlier for second progression-free survival or time to death.

[0082] There were more adverse events, especially anemia, in the abiraterone acetate and olaparib arm of the study. However, the adverse event profiles for the abiraterone acetate and olaparib arms were consistent with their known individual toxicity profiles, and do not suggest that the combination therapy increases the toxicity of either drug. In a Phase II study of abiraterone acetate and olaparib versus abiraterone acetate and placebo in mCRPC, more patients in the abiraterone acetate and olaparib arm had cardiovascular events. Reassuringly, no difference in cardiovascular events was observed in this study, suggesting that the previously observed imbalance may have been due to the small population size of the Phase II study. There was a numerical imbalance in pulmonary events between the study arms, with one event being fatal in the abiraterone acetate and olaparib arm, but no events led to the discontinuation of olaparib or abiraterone acetate treatment. Pulmonary events have been observed in trials of other PARP inhibitors in mCRPC (6% of patients had pulmonary embolism in the TALAPRO-1 trial). Similar disparities in pulmonary events have not been observed in olaparib trials in other tumor types. Currently, the mechanism of this effect in the mCRPC population is unknown.

[0083] At the interim analysis, abiraterone acetate and olaparib provided significantly longer imaging-based progression-free survival than abiraterone acetate and placebo in treatment-naive patients with mCRPC enrolled regardless of HRRm status in the first-line setting. Favorable trends for TFST, PFS2, and overall survival at this interim data cut, as well as exploratory endpoints of ORR and PSA response, further support the treatment benefit of abiraterone acetate and olaparib over abiraterone acetate and placebo in the entire analyzed patient population. Although there were more adverse events in the abiraterone acetate and olaparib arm, they were as expected for the individual drugs, generally manageable with dose interruptions and reductions, and no harm to HRQoL was reported. These results demonstrate the clinical benefit of olaparib in combination with abiraterone acetate in a broad, HRRm-unselected population of patients with mCRPC. Such combined treatment effects could potentially change clinical practice in the first-line mCRPC setting.

[0084] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light of them will be suggested to those skilled in the art and are to be incorporated within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

1. A medicament comprising olaparib, or a salt, hydrate, solvate, or prodrug thereof, for treating prostate cancer in a subject, wherein the treatment comprises the simultaneous, sequential, or simultaneous administration of olaparib, or a hydrate, solvate, or prodrug thereof, and abiraterone acetate, or a salt thereof, to the subject, wherein the subject has not been selected for an HRR gene mutation in the cancer, and wherein the subject has a progression-free survival that is at least about 6 months longer than a subject receiving abiraterone acetate or a salt thereof alone.

2. The pharmaceutical composition of claim 1, wherein the cancer has metastasized.

3. The pharmaceutical composition according to claim 2 , wherein the metastasis is to bone and / or lymph nodes.

4. The pharmaceutical composition of claim 2, wherein the metastasis is visceral.

5. The pharmaceutical composition of claim 1, wherein the cancer is mCRPC.

6. The pharmaceutical composition of claim 1, wherein the cancer cells are wild-type in one or more HRR genes.

7. The pharmaceutical of claim 1 , wherein the cancer cells contain one or more HRR gene mutations.

8. The method of claim 1, wherein the cancer is mCRPC containing one or more HRR gene mutations.

9. The pharmaceutical composition of claim 7, wherein the HRR gene mutation is selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L gene mutations; or the cancer cells contain BRCA1, BRCA2, and / or ATM gene mutations; or the cancer cells contain BRCA1 and / or BRCA2 gene mutations.

10. The pharmaceutical described in claim 8, wherein the HRR gene mutation is selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L gene mutations; or the cancer cells contain BRCA1, BRCA2, and / or ATM gene mutations; or the cancer cells contain BRCA1 and / or BRCA2 gene mutations.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the prostate cancer is mCRPC and the subject is treatment-naive.

12. The method of claim 11, wherein the subject has not received prior taxane-based chemotherapy, and optionally the taxane-based chemotherapy is docetaxel.

13. The pharmaceutical composition of any one of claims 1 to 10, wherein the subject has not previously received a novel hormonal chemotherapy, and optionally, the novel hormonal agent is abiraterone acetate or a salt thereof.

14. The pharmaceutical composition of any one of claims 1 to 10, wherein the subject has previously received taxane-based chemotherapy.

15. The pharmaceutical composition of any one of claims 1 to 10, wherein the subject has previously undergone a novel hormonal chemotherapy, and optionally the novel hormonal agent is enzalutamide or abiraterone acetate or a salt thereof.

16. The method of any one of claims 1 to 6, wherein the cancer is mCRPC that is wild-type in one or more HRR gene mutations, and the subject has not previously received docetaxel.

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