Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial

Background 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. Methods 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. Findings 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. Interpretation 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

Radiotherapy in testicular germ cell tumours – a literature review

Testicular germ cell tumours (GCT) represent about 1–2% of malignant in men. The essential therapeutic option for early-stage GCT is radical orchiectomy (RO), except in situ ations that require immediate chemotherapy in patients with a massive dissemination and unequivocally elevated levels of tumour markers. Postoperative radiotherapy (PORT) in patients with testicular seminoma in Clinical Stage I (CS I) is one of the treatment options next to active surveillance (AS) and chemotherapy (CHTH). Regardless of the procedure, five-year survival in this group of patients ranges between 97% and 100%. In the article, we present the literature review pertinent to therapeutic options, with a focus on radiotherapy. We have searched MEDLINE (PubMed) for all studies on patients with GCT treated with radiation therapy during the last 20 years, and the current therapeutic recommendations. We used the following keywords: germ cell tumours, testis, seminoma, non-seminoma, radiotherapy, outcome

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial

Background Results of this double-blind, phase 2 trial showed patients with metastatic castration-resistant prostate cancer given olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here, we present an exploratory analysis of pain and health-related quality of life (HRQOL). Methods This double-blind, randomised, placebo-controlled, phase 2 trial was conducted across 41 urological oncology sites in 11 countries in Europe and North America. Eligible patients were aged 18 years or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of previous chemotherapy. Metastatic castration-resistant prostate cancer was defined as increasing prostate-specific antigen (PSA) concentration or other signs of disease progression despite androgen-deprivation therapy and serum testosterone concentrations at castrate levels (≤50 ng/dL), and with at least one metastatic lesion on bone scan, CT, or MRI. Eligible patients were randomly assigned (1:1) to receive oral olaparib (300 mg twice per day) plus oral abiraterone (1000 mg once a day) and oral prednisone or prednisolone (5 mg twice a day) or placebo plus abiraterone (1000 mg once a day) and prednisone or prednisolone (5 mg twice a day). Randomisation was done without stratification and by use of an interactive voice or web response system. A randomised treatment kit ID number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has previously been reported. HRQOL was a prespecified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), single-item worst bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 five-dimension five level (EQ-5D-5L) assessment at baseline, at weeks 4, 8, and 12, then every 12 weeks until treatment discontinuation. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain and FACT-P Total Outcome Index (TOI) scale scores, time to deterioration in BPI-SF worst pain and worst bone pain, and assessment of the EQ-5D-5L pain and discomfort domain. All analyses were exploratory and done in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently go on to receive study treatment), with the exception of mean baseline and total change from baseline analyses, for which we used the population who had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients. Findings Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded, and 142 were enrolled and randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). Data cutoff was Sept 22, 2017. Median follow-up was 15·9 months (IQR 8·1–25·5) in the olaparib plus abiraterone group and 24·5 months (8·1–27·6) in the placebo plus abiraterone group. Questionnaire compliance was generally high (43–100%). Least-squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P TOI remained stable across all visits for patients in both treatment groups. Adjusted mean change in FACT-P TOI from baseline across all visits was −0·10 (95% CI −2·50 to 2·71) in the olaparib plus abiraterone group and −1·20 (−4·15 to 1·74) in the placebo plus abiraterone group (difference 1·30, 95% CI −2·70 to 5·30; p=0·52). Time to deterioration in pain was similar in both groups (BPI-SF worst pain HR 0·90 [95% CI 0·62–1·32], p=0·30; worst bone pain HR 0·85 [0·59–1·22], p=0·18). Improvement rates in the pain and discomfort domain of the EQ-5D-5L were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported an improvement compared to the placebo plus abiraterone group. Interpretation In these prespecified exploratory analyses, there was no significant difference in pain or HRQOL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the olaparib plus abiraterone combination. These results suggest that the improved survival benefits observed when combining olaparib with abiraterone does not result in different HRQOL compared with placebo plus abiraterone. Phase 3 studies are required to validate these results

Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL):a randomised, double-blind, placebo-controlled phase 3 trial

International audienceBACKGROUND:Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.METHODS:In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208.FINDINGS:1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group.INTERPRETATION:Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted.FUNDING:Celgene Corporation