Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial.

Background: The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial.
Methods: In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543.
Findings: Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; p _nominal =0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; p _nominal =0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; p _nominal =0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; p _nominal =0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; p _nominal =0·0013).
Interpretation: Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound.
Funding: AstraZeneca and Merck Sharp & Dohme.
Competing Interests: Declaration of interests FS reports grants from AstraZeneca and Merck Sharp & Dohme for the submitted work; grants from Astellas, Bayer, Bristol Myers Squibb, Janssen, Pfizer, and Sanofi; consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, and Sanofi; honoraria from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, and Sanofi; and is an advisory board member for Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. GR reports an advisory board role for Gilead; meeting support from Astellas, AstraZeneca, and Janssen; honoraria from AstraZeneca, Janssen, and Sanofi; and consulting fees from Astellas, AstraZeneca, and Merck Sharp & Dohme. GP reports consultant fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Janssen, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi; and honoraria from Bristol Myers Squibb, Eisai, Janssen, Ipsen, Merck Sharp & Dohme, and Pfizer. NS reports support for research site and medical writing from AstraZeneca and Merck Sharp & Dohme for the submitted work; consulting fees from AstraZeneca and Merck; and is an advisory board member for AstraZeneca and Merck. KF reports consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Novartis, Orion, and Sanofi; and honoraria from Astellas, AstraZeneca, Bayer, Janssen, Novartis, and Sanofi. AT-V reports medical writing support from and holds an advisory role with AstraZeneca, associated with the submitted work; grants from Bayer, Ipsen, and Pfizer; consulting fees from Astellas, AstraZeneca, BMS, Ipsen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, and Roche; meetings support from Astellas, AstraZeneca, Bristol Myers Squibb, Ipsen, Johnson & Johnson, Merck Sharp & Dohme, and Roche; is a data safety monitoring board member for the BIONIKK trial (NCT02960906); and is a member of the steering committee of the French Genitourinary Tumour Group academic group. GG reports honoraria from Amgen, Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen Oncology, MSD Oncology, Sanofi/Aventis; meetings support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Pfizer, Janssen Oncology, and Sanofi; and is an advisory board member for AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen Oncology, Merck Sharp & Dohme Oncology, Pfizer, and Sanofi/Aventis. NM holds an advisory board role for Chugai, Janssen, and Sanofi; payment or honoraria from Janssen and Sanofi; grant and institution funding from Astellas, Amgen, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Takeda, and Taiho. DC reports consulting or advisory roles for Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen Oncology, Lilly, Merck Sharp & Dohme Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi; research funding by Janssen Oncology; and travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, Pfizer, and Roche. MH reports funding and medical writing support from AstraZeneca for the submitted work; and grants, consulting fees, and honoraria from AstraZeneca. AD, CG, JK, and AK are employees of and have stock ownership with AstraZeneca. CP is an employee of Merck Sharp & Dohme, a subsidiary of Merck and holds stock ownership in Merck. JdB reports funding and medical writing support from AstraZeneca and Merck Sharp & Dohme for the submitted work; grants from Amgen, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Harpoon, ImCheck Therapeutics, Janssen, Merck Sharp & Dohme, Serono, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; royalties or licences (no personal income) from abiraterone, poly(adenosine diphosphate–ribose) polymerase inhibition, and P13K/AKT; consulting fees from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex; grants and personal fees from AstraZeneca during the study; personal fees and non-financial support from Astellas Pharma; grants, personal fees and non-financial support from AstraZeneca; personal fees from Bayer, Boehringer Ingelheim, Genentech/Roche, Merck Serono, Merck Sharp & Dohme, Janssen, and Pfizer; personal fees and non-financial support from Sanofi; non-financial support from Genmab, GlaxoSmithKline, Orion, Qiagen, Taiho Pharmaceutical, and Vertex; and personal fees from Cellcentric, Daiichi, GlaxoSmithKline, Menarini/Silicon Biosystems, and Sierra Oncology outside the submitted work. In addition, JdB has a patent for abiraterone and steroids for the treatment of prostate cancer with royalties paid to Janssen, and a patent for PARP inhibitors and DNA repair defects with royalties paid to AstraZeneca. All other authors declare no competing interests.
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