610O - Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations

Background

The phase 3 randomized, open-label PROfound trial (NCT02987543) met its primary endpoint of significantly prolonged radiographic progression-free survival with olaparib vs physician’s choice of enzalutamide or abiraterone (control arm) in pts with mCRPC with progression on prior therapy and alterations in BRCA1, BRCA2 or ATM (Cohort A), and in the overall population (Cohorts A+B) with alterations in any of 15 prespecified genes with a direct or indirect role in HRR. Final OS data are reported.

Methods

Men with mCRPC and disease progression on a prior new hormonal agent (eg enzalutamide or abiraterone) were randomized 2:1 to olaparib or control treatment. Pts could crossover to olaparib upon radiographic disease progression. A prespecified key secondary endpoint was OS in Cohort A, analysed by alpha-controlled stratified log-rank test.

Results

At data cut-off (20 March 2020), median final OS in Cohort A was significantly longer with olaparib than with physician’s choice of enzalutamide or abiraterone (HR 0.69; 95% CI 0.50, 0.97; P=0.0175), with a trend towards improvement in the overall population (HR 0.79; 95% CI 0.61, 1.03; nominal P=0.0515). Of pts in the control arm, 56 (67%) in Cohort A and 86 (66%) in the overall population crossed over to olaparib. Longer follow-up yielded no new safety signals. Table: 610O

*0.047 alpha spent at final OS analysis; ^†Nominal; ^‡Censored pts. CI, confidence interval; HR, hazard ratio; OS overall survival

Conclusions

PROfound is the first phase 3 trial to show a PARP inhibitor benefit in alpha-controlled OS analyses. Despite extensive crossover from the control arm, olaparib conferred a statistically significant and clinically meaningful prolongation of OS vs sequential therapy with enzalutamide or abiraterone in men with mCRPC with progression on prior therapy and alterations in BRCA1, BRCA2 or ATM, with a 31% reduction in the risk for death.

Clinical trial identification

NCT02987543.

Editorial acknowledgement

Medical writing assistance was provided by Jacqueline Kolston, PhD, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).

Legal entity responsible for the study

AstraZeneca and Merck.

Funding

AstraZeneca and Merck.

Disclosure

J.S. de Bono: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy, Licensing/Royalties, Patent WO 20 0 5 0 53662 on DNA damage repair inhibitors for treatments of cancer: AstraZeneca; Advisory/Consultancy: Bayer Healthcare; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Daiichi Sankyo Company; Advisory/Consultancy: Genentech; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy, Licensing/Royalties, Patent US560 4213 on 17 substituted steroids useful in cancer treatment: Janssen Global Services; Advisory/Consultancy: Menarini Silion Biosystems; Advisory/Consultancy: Merck; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Orion Corporation; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Qiagen Sciences; Advisory/Consultancy: Sanofi Aventis US; Advisory/Consultancy: Sierra Oncology; Advisory/Consultancy: Taiho Pharmaceuticals; Advisory/Consultancy: Vertex Pharmaceuticals. J. Mateo: Advisory/Consultancy: Amgen; Advisory/Consultancy: Clovis Oncology; Advisory/Consultancy: Janssen Pharmaceuticals; Speaker Bureau/Expert testimony: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca. K. Fizazi: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: AAA; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Curevac; Honoraria (self), Advisory/Consultancy: Essa; Honoraria (self), Advisory/Consultancy: Janssen Biotech; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Orion Corporation; Honoraria (self), Advisory/Consultancy: Sanofi Aventis US. F. Saad: Advisory/Consultancy, Non-remunerated activity/ies: AstraZeneca; Advisory/Consultancy, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory/Consultancy, Non-remunerated activity/ies: Merck; Advisory/Consultancy, Non-remunerated activity/ies: Pfizer; Advisory/Consultancy, Non-remunerated activity/ies: Myovant; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies: Sanofi; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies: Janssen; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies: Bayer; Honoraria (self), Advisory/Consultancy, Non-remunerated activity/ies: Astellas. N. Shore: Advisory/Consultancy: Amgen; Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Dendreon Pharmaceuticals; Advisory/Consultancy: Ferring; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: Merck; Advisory/Consultancy: MDxHealth; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Tolmar Pharmaceuticals; Advisory/Consultancy: Clovis. S. Sandhu: Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Endocyte; Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Serono. K.N. Chi: Research grant/Funding (institution): BC Cancer; Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self), Advisory/Consultancy: Janssen Pharmaceuticals; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Point Biopharma. O. Sartor: Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Invitae; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Clovis Oncology. N. Agarwal: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Astellas Pharma; Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Clovis Oncology; Honoraria (self), Advisory/Consultancy: CRISPR; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy: EMD Serono; Honoraria (self), Advisory/Consultancy: Exelixis; Honoraria (self), Advisory/Consultancy: Foundation Medicine; Honoraria (self), Advisory/Consultancy: Genentech; Honoraria (self), Advisory/Consultancy: Janssen Biotech; Honoraria (self), Advisory/Consultancy: Medivation; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Nektar Pharma; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Pharmacyclics LLC (an AbbVie company); Honoraria (self), Advisory/Consultancy: Seattle Genetics. D. Olmos: Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses, Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Bayer Healthcare; Advisory/Consultancy: Clovis Oncology; Travel/Accommodation/Expenses, Non-remunerated activity/ies: F. Hoffmann-La Roche; Advisory/Consultancy, Non-remunerated activity/ies: Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Sanofi. A. Thiery-Vuillemin: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Ipsen Pharma SAS; Advisory/Consultancy: Janssen Biotech; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi Aventis US; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: F. Hoffmann-La Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Janssen Pharmaceuticals. P. Twardowski: Honoraria (self), Speaker Bureau/Expert testimony: Astellas Pharma; Honoraria (self), Speaker Bureau/Expert testimony: Janssen Biotech. M. Ozguroglu: Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Astellas; Honoraria (self): Novartis; Honoraria (self): Roche; Travel/Accommodation/Expenses: Bristol-Myers Squibb. J. Kang: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. J. Burgents: Full/Part-time employment, Within last 5 years: AstraZeneca; Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck Sharp & Dohme Corporation. C. Gresty: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. C. Corcoran: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. C.A. Adelman: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. M. Hussain: Honoraria (self), Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bayer; Honoraria (self): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Honoraria (self), Travel/Accommodation/Expenses: Astellas; Honoraria (self): Physicians' Education Resource; Honoraria (self): Projects in Knowledge; Honoraria (self): Sanofi/Genzyme; Honoraria (self): Phillips Gilmore Oncology; Honoraria (self): Research to Practice; Honoraria (self): MLI Peer Review; Research grant/Funding (institution): Prostate Cancer Clinical Trials Consortium. All other authors have declared no conflicts of interest.