At the primary analysis of PROpel (NCT03732820; data cut-off [DCO]: 30/07/21), abi + ola significantly prolonged radiographic progression-free survival (rPFS) vs pbo + abi in 1L mCRPC (HR 0.66, 95% CI 0.54–0.81; P<0.0001). Overall survival (OS) trended towards a benefit with abi + ola vs abi + pbo (28.6% maturity; HR 0.86, 95% CI 0.66–1.12). We report biomarker analysis from the primary analysis and updated overall survival and safety data from a planned OS interim analysis (DCO2).
PROpel is a double-blind, pbo-controlled trial. 796 pts were randomized 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone or prednisolone (5 mg bid), irrespective of homologous recombination repair gene mutation (HRRm) status. The primary endpoint was rPFS by investigator assessment. OS was a key secondary endpoint. Aggregated results from tumour tissue (FoundationOne®CDx) and circulating tumour DNA (FoundationOne®Liquid CDx) tests were used to classify pts HRRm status.
Pts with HRRm, including BRCAm, were balanced between treatment arms and rPFS favoured abi + ola for all biomarker subgroups, including pts with non-HRRm, HRRm and BRCAm status (HR 0.76, 0.50 and 0.23 respectively; Table). Sensitivity analysis of rPFS by blinded independent central review was consistent. At DCO2 (14/03/22) rPFS was consistent with the primary analysis (25.0 vs 16.4 months; HR 0.67, 95% CI 0.56–0.81). A trend towards improved OS with abi + ola vs abi + pbo continued (maturity 40%; HR 0.83; 95% CI 0.66–1.03). Safety and tolerability results remained stable.
| Biomarker subgroup analyses | |||||||
| Abi + ola (N=399) | Abi + pbo (N=397) | HR (95% CI) | |||||
| n | Events (%) | Median rPFS (months) | n | Events (%) | Median rPFS (months) | ||
| ITT population | 399 | 168 (42) | 24.8 | 397 | 226 (57) | 16.6 | 0.66 (0.54‒0.81) |
| Non-HRRm | 279 | 119 (43) | 24.1 | 273 | 149 (55) | 19.0 | 0.76 (0.60‒0.97) |
| HRRm* | 111 | 43 (39) | NR | 115 | 73 (64) | 13.9 | 0.50 (0.34‒0.73) |
| Non-BRCAm | 343 | 148 (43) | 24.1 | 350 | 194 (55) | 19.0 | 0.76 (0.61‒0.94) |
| BRCAm† | 47 | 14 (30) | NR | 38 | 28 (74) | 8.4 | 0.23 (0.12‒0.43) |
Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D and RAD54L
†BRCA1 and/or BRCA2
ITT, intention-to-treat, NR, not reached
HRRm unknown pts (n=18) were excluded from the analysis.
Meaningful rPFS improvement of ≥5 months was observed with abi + ola vs abi + pbo in all assessed biomarker subgroups. Updated results show a continuing trend towards improved OS and support a superior clinical benefit with abi + ola vs abi + pbo as 1L therapy for pts with mCRPC.
NCT03732820.
Medical writing support was provided by Kirstin Spence, PhD, at Mudskipper Business Ltd., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
AstraZeneca.
This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA who are codeveloping olaparib.
M. Oya: Financial Interests, Personal, Advisory Role, Honoraria: Bayer; Financial Interests, Personal, Funding, Honoraria: Bristol Myers Squibb, Ono Pharmaceutical, AstraZeneca, Astellas, Takeda; Financial Interests, Personal and Institutional, Research Grant, Honoraria: Novartis, Pfizer. A.J. Armstrong: Financial Interests, Personal and Institutional, Advisory Role, Research funding: Janssen, Novartis, Myovant Sciences, Bayer, Dendreon, Merck, AstraZeneca, FORMA Therapeutics, Dendreon; Financial Interests, Personal, Advisory Role: Exelixis, GoodRx; Financial Interests, Personal and Institutional, Advisory Board, Research funding; Travel fees: Astellas Scientific and Medical Affairs Inc; Financial Interests, Personal, Advisory Role, Research funding: Pfizer, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Gilead Sciences, Roche/Genentech, Constellation Pharmaceuticals, Amgen; Financial Interests, Personal, Research Grant: BeiGene; Financial Interests, Institutional, Royalties: Circulating tumor cell novel capture technology. A. Thiery-Vuillemin: Financial Interests, Personal, Advisory Board, & public speaking: pfizer, astrazeneca, Janssen, Ipsen, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Sanofi, Novartis, Roche/Genentech, MSD, Astellas Pharma; Financial Interests, Institutional, Funding: pfizer, ipsen, bayer; Financial Interests, Institutional, Invited Speaker: Pfizer, AstraZeneca, Sanofi JNJ, Novartis, ipsen, roche, BMS, MSD, Astellas Pharma, excelixis, UNICANCER / GETUG, incyte; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, BMS; Non-Financial Interests, Personal, Member: ASCO, GETUG; Other, Personal, Other, Travel, Accommodations: Roche, MSD, JNJ, BMS, astrazeneca, pfizer, Astellas Pharma, Ipsen. N. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, PreView, Sanofi Genzyme, Speciality Networks, Sesen Bio, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Sema4, Tempus, Photocure, Vaxiion, Asieris. 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. Ç. Arslan: Financial Interests, Personal and Institutional, Advisory Role, Speaker's bureau; research funding; travel expenses: Amgen, AstraZeneca, Bristol Myers Squib, Janssen, Novartis; Financial Interests, Personal and Institutional, Advisory Role, Speaker's bureau; travel expenses: Pfizer, Teva; Financial Interests, Institutional, Research Grant: Incyte, Henlius, Yuhan, Lilly; Financial Interests, Personal and Institutional, Research Grant, Travel expenses: Merck. 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, Invited Speaker: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Personal, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Personal, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Personal, Leadership Role: Castration-resistant Prostate Cancer Registry. F. Parnis: Financial Interests, Personal, Advisory Role: Ipsen, Janssen Oncology, Merck Serono. F. Constans Schlurmann: Financial Interests, Personal, Advisory Role, Honoraria; travel expenses: AAA, AstraZeneca, Astellas, Bayer, BMS, Janssen, MSD, Pfizer. M. Sugimoto: Financial Interests, Personal, Research Grant, Honoraria; travel expenses: Janssen Pharmaceutical, AstraZeneca, Astellas Pharma; Financial Interests, Personal, Funding, Honoraria: Takeda Pharmaceutical; Financial Interests, Personal, Research Grant, travel expenses: BMS, MSD; Financial Interests, Personal, Research Grant: Pfizer; Other, Personal, Other, Travel expenses: Bayer. O. Sartor: Financial Interests, Personal and Institutional, Advisory Role, Research grant: Advanced Accelerator Applications, AstraZeneca, Bayer, Constellation, Janssen, Progenics, Tenebio; Financial Interests, Personal, Advisory Role: Astellas, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Myovant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, POINT Biopharma, Pfizer, Sanofi, Telix, Theragnostics; Financial Interests, Institutional, Research Grant: Amgen, Endocyte, Invitae, Lantheus, Merck. Y. Liu: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck&Co. C. Desai: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. P.M.D. Del Rosario: Financial Interests, Personal, Full or part-time Employment, Stocks: AstraZeneca. N. Clarke: Financial Interests, Personal, Funding, Honoraria: Janssen, Bayer; Financial Interests, Personal, Advisory Board, Consulting fees; Advisory Board; Honoraria: AstraZeneca. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Sanofi, Pfizer, Myovant, Novartis; Financial Interests, Institutional, Invited Speaker: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer. All other authors have declared no conflicts of interest.