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Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.

Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.

PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis. This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0–1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system–interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting. Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1–40·3) for olaparib plus abiraterone and 36·5 months (33·8–40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4–not reached) with olaparib plus abiraterone and 34·7 months (31·0–39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67–1·00; p=0·054). The most common grade 3–4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related. Overall survival was not significantly different between treatment groups at this final prespecified analysis. Supported by AstraZeneca and Merck Sharp & Dohme.

Among men with high-risk, nonmetastatic, castration-resistant prostate cancer, the addition of enzalutamide to androgen-deprivation therapy improved overall survival by nearly a year as compared with ADT alone: median survival was 67 months with enzalutamide plus ADT and 56 months with ADT alone.

Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8–20·4) with olaparib and abiraterone and 8·2 months (5·5–9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44–0·97, p=0·034). The most common grade 1–2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer. AstraZeneca.

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. Pfizer/Medivation.

The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents, including docetaxel, sipuleucel T, abiraterone, cabazitaxel, and enzalutamide. Enzalutamide (previously MDV-3100) is a novel oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. The randomized phase III AFFIRM study demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression in patients with progressive mCRPC who had received prior treatment with docetaxel. Enzalutamide was well tolerated and there were comparable incidences of grade 3 or greater adverse events reported for the enzalutamide and placebo control arms in AFFIRM. Unlike some other treatments for mCRPC, enzalutamide does not require administration with steroids. The ongoing randomized phase III PREVAIL trial will investigate the efficacy and safety of enzalutamide in chemotherapy-naïve patients with mCRPC. Additional trials are investigating the use of enzalutamide in a number of disease settings.

In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223. We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16. Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5–11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13–not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months–NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11–15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14–NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8–14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months–NA) than for patients with an ECOG PS of 1 (median 13 months, 11–NA) or an ECOG PS of 2 or more (median 7 months, 5–11); and for patients with no reported baseline pain (median NA, 16 months–NA) than for those with mild pain (median 14 months, 13–NA) or moderate–severe pain (median 11 months, 9–13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months–NA) than in those who did not receive these agents (median 13 months, 12–16), and in patients who received radium-223 plus denosumab (median NA, 15 months–NA) than in patients who received radium-223 without denosumab (median 13 months, 12–NA). Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials. Pharmaceutical Division of Bayer.

Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations. Janssen Research & Development.

Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0–25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4–24·8) in the radium-223 group and 26·0 months (21·8–28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917–1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3–4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia). The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination. Bayer.