1805P - Efficacy of olaparib (ola) + abiraterone (abi) vs placebo (pbo) + abi in the non-BRCA mutation (non-BRCAm) subgroup of patients (pts) with metastatic castration-resistant prostate cancer (mCPRC) in the PROpel trial

Background

PROpel (NCT03732820) met its primary endpoint with a significant investigator-assessed radiographic progression-free survival (IA rPFS) benefit with ola + abi vs pbo + abi in the intention-to-treat (ITT) population in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). At final pre-specified analysis there was a trend to improved overall survival (OS) with ola + abi vs pbo + abi (median 42.1 vs 34.7 months [m]; HR 0.81, 95% CI 0.67–1.00; P=0.0544). The greatest magnitude of benefits was seen in the BRCAm subgroup. Post hoc exploratory analyses were conducted to further investigate outcomes in non-BRCAm pts.

Methods

PROpel was a phase 3 double-blind trial. Pts were enrolled irrespective of biomarker status and randomized 1:1 to receive ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone/prednisolone (5 mg bid). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. Aggregated tumour tissue (FoundationOne®CDx) and ctDNA (FoundationOne®Liquid CDx) test results, performed after randomization and before primary analysis, were used to classify pt mutation status. Non-BRCAm pts had no positive BRCAm test result and at least 1 negative BRCAm tissue or ctDNA result.

Results

In the non-BRCAm subgroup (n=693), there was a meaningful clinical benefit across endpoints for pts treated with ola + abi (Table). Safety profile of the combination was consistent with the ITT population. Within the non-BRCAm subgroup, analyses by baseline clinical characteristics showed consistent effect and will be presented. Table: 1805P

*DCO1; 30/7/21 ^†DCO3; 12/10/22 AE, adverse event; DCO, data cutoff; NC, not calculable; ORR, objective response rate; PSA, prostate-specific antigen

Conclusions

Exploratory analyses across multiple endpoints support a clinically meaningful benefit with ola + abi vs pbo + abi in non-BRCAm pts and a safety profile consistent with the overall ITT population.

Clinical trial identification

NCT03732820.

Editorial acknowledgement

Medical writing assistance was provided by Kirstin Spence, PhD, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry. N.W. Clarke: Financial Interests, Personal, Other, Honoraria: Janssen, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Travel, accommodation, expenses: AstraZeneca. A.J. Armstrong: Financial Interests, Institutional, Advisory Role: Janssen, Novartis, Myovant Sciences, Bayer, Exelixis, Dendreon, Merck, GoodRx, AstraZeneca, FORMA Therapeutics, Astellas Scientific and Medical Affairs Inc, Pfizer, BMS; Financial Interests, Institutional, Research Funding: Gilead Sciences, Roche/Genentech, BMS, AstraZeneca, FORMA Therapeutics, Astellas Pharma, Constellation Pharmaceuticals, Dendreon, Pfizer, Amgen, Novartis, Janssen Oncology, Merck, Bayer, BeiGene; Financial Interests, Institutional, Royalties: Circulating tumor cell novel capture technology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Astellas Scientific and Medical Affairs Inc.. M. Oya: Financial Interests, Personal, Other, Honoraria: Bayer, BMS, Novartis, Ono Pharmaceutical, Pfizer, AstraZeneca, Astellas, Takeda; Financial Interests, Institutional, Advisory Role: Bayer; Financial Interests, Institutional, Research Funding: Novartis, Pfizer. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Propella, PreView, Sanofi Genzyme, Speciality Networks, Sesen Bio, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Photocure, Vaxiion, Asieris, Alessa Therapeutics, Akido, Arquer, Fize medical, GConcology, Genentech, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Profound, Promaxo, Protara, Vessi; Financial Interests, Personal, Member of Board of Directors: Photocure. G. Procopio: Financial Interests, Personal, Advisory Board, consultant fees: Astellas, AstraZeneca, Bayer, BMS, Janssen, Ipsen, Merck, MSD, Novartis, Pfizer; Financial Interests, Institutional, Research Grant, research funding for no profit clinical trial: Ipsen. J.D.C. Guedes: Financial Interests, Personal, Other, Honoraria: Merck, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Funding: Agenus, Amgen, AstraZeneca, Bayer, BMS, BRAVA, Daiichi Sankyo, Eurofarma, Genentech, HUYABIO, Incyte, Lilly, MSD, Pfizer, PTC, Roche, Sanofi, Takeda; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Gilead. C. Arslan: Financial Interests, Institutional, Invited Speaker: BMS, Bayer, Amgen, Teva, Lilly, Johnson &Johnson; Financial Interests, Institutional, Advisory Board: Novartis, Merck, AstraZeneca, Johnson &Johnson, Lilly, Astellas, Teva, BMS; Financial Interests, Institutional, Local PI: Roche, Novartis, BMS, Merck, AstraZeneca, Nektar, Johnson &Johnson, Lilly, Amgen, Bayer, Incyte. F. Parnis: Financial Interests, Personal, Invited Speaker: Bayer. F. Schlürmann: Financial Interests, Personal, Other, Honoraria: Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer; Financial Interests, Institutional, Advisory Role: Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Advanced Accelerator Applications, AstraZeneca, Astellas, Bayer. M. Sugimoto: Financial Interests, Personal, Other, Honoraria: Astellas, AstraZeneca, Janssen, Takeda. D. Castellano: Financial Interests, Institutional, Advisory Role: Janssen Oncology, Roche/Genentech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD Oncology, Bayer, Lilly, Sanofi, Pierre Fabre, Boehringer Ingelheim; Financial Interests, Institutional, Research Funding: Janssen Oncology; Financial Interests, Personal, Other, Travel/accommodation support: Pfizer, Roche, BMS, AstraZeneca Spain. Y. Urun: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen Oncology, Pfizer, BMS, Roche, MSD; Financial Interests, Personal, Invited Speaker: Astellas, Janssen Oncology, Pfizer, BMS, Roche, Amgen; Financial Interests, Personal and Institutional, Local PI: BMS, AstraZeneca, MSD, Janssen, Roche. C. Hosius: Financial Interests, Institutional, Full or part-time Employment: Merck Sharp & Dohme; Financial Interests, Personal, Stocks or ownership: Merck. C. Desai, A. Degboe: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks or ownership: AstraZeneca. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Sanofi, Pfizer, Myovant, Novartis, AstraZeneca, Merck, Myovant; Financial Interests, Institutional, Local PI: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeneca. All other authors have declared no conflicts of interest.