Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer

Hussain, Maha M.D.
Mateo, Joaquin M.D.
Fizazi, Karim M.D.
Saad, Fred M.D.
Shore, Neal M.D.
Sandhu, Shahneen M.D.
Chi, Kim N. M.D.
Sartor, Oliver M.D.
Agarwal, Neeraj M.D.
Olmos, David M.D.
Thiery-Vuillemin, Antoine M.D.
Twardowski, Przemyslaw M.D.
Roubaud, Guilhem M.D.
Özgüroğlu, Mustafa M.D.
Kang, Jinyu M.D.
Burgents, Joseph Ph.D.
Gresty, Christopher M.Sc.
Corcoran, Claire Ph.D.
Adelman, Carrie A. Ph.D.
de Bono, Johann M.D.

From the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (M.H.); Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona (J.M.), the Spanish National Cancer Research Center, Madrid (D.O.), and Instituto de Investigación Biomédica de Málaga, Málaga (D.O.) — all in Spain; Institut Gustave Roussy, University of Paris Saclay, Villejuif (K.F.), the Department of Medical Oncology, Centre Hospitalier Universitaire Besançon, Besançon (A.T.-V.), and the Department of Medical Oncology, Institut Bergonié, Bordeaux (G.R.) — all in France; Centre Hospitalier de l'Université de Montréal–Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal (F.S.), and BC Cancer Agency, Vancouver (K.N.C.) — both in Canada; Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S.S.); Tulane University School of Medicine, New Orleans (O.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (N.A.); John Wayne Cancer Institute, Santa Monica, CA (P.T.); Istanbul University–Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey (M.O.); AstraZeneca, Global Medicines Development, Oncology, Gaithersburg, MD (J.K.); Merck, Kenilworth, NJ (J.B.); and Global Medicines Development, Oncology (C.G.), Precision Medicine and Biosamples, R&D Oncology (C.C.), and Translational Medicine (C.A.A.), AstraZeneca, Cambridge, and the Institute of Cancer Research and Royal Marsden, London (J.B.) — both in the United Kingdom.

^*A complete list of the investigators in the PROfound trial is provided in the Supplementary Appendix, available at NEJM.org.

Address reprint requests to Dr. Hussain at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Superior St., Suite 3-107, Chicago, IL 60611, or at [email protected].

Supported by AstraZeneca and Merck Sharp and Dohme (a subsidiary of Merck).

Dr. Hussain reports receiving grant support, advisory board fees, and travel support from Pfizer, Bayer, and Genentech/Roche, grant support, advisory board fees, and lecture fees from AstraZeneca, grant support, paid to Northwestern University, from Arvinas, lecture fees and travel support from Astellas, lecture fees from Physicians' Education Resource, Sanofi/Genzyme, Research to Practice, and OncLive, honoraria from Projects in Knowledge, advisory board fees from Bristol-Myers Squibb and Daiichi Sankyo, fees for conducting an interview with UroToday, and holding patents UM-14437/US-1/PRO 60/923,385 and UM-14437/US-2/ORD12/101,753 on systems and methods for tissue imaging, patent 224990/10-016P2/31173361/481/671 on a method of treating cancer, and patent 11764665.4-1464 on dual inhibition of MET and vascular endothelial growth factor for the treatment of castration-resistant prostate cancer and osteoblastic bone metastases; Dr. Mateo, receiving grant support, paid to his institution, advisory board fees, fees for serving on a speakers bureau, and access to materials from AstraZeneca, grant support, paid to his institution, from Pfizer Oncology, advisory board fees, fees for serving on a speakers bureau, and travel support from Janssen Oncology and Astellas, and advisory board fees from Clovis Oncology, Merck, Merck Sharp and Dohme, Roche, and Amgen; Dr. Fizazi, receiving fees for serving as an investigator, paid to his institution, from Astellas, Janssen, Sanofi, Bayer, AAA Pharma, and Clovis, advisory board fees from Orion and CureVac, and advisory board fees and fees for participating in a symposium from Merck Sharp and Dohme; Dr. Saad, receiving grant support, consulting fees, advisory board fees, lecture fees, and writing assistance from Sanofi, Janssen, Bayer, and Astellas, grant support, consulting fees, and writing assistance from Bristol-Myers Squibb, Merck, Pfizer, and Myovant, and grant support, consulting fees, advisory board fees, and lecture fees from AstraZeneca; Dr. Shore, receiving fees for serving as an investigator and consulting fees from Abbvie, Ambry, Amgen, Astellas, AstraZeneca, Bayer, Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, FerGene, Ferring, Foundation Medicine, Invitae, Janssen, MDXHealth, Merck, Myriad, Pfizer, Platform Q, Sanofi/Genzyme, Tolmar, Bristol-Myers Squibb, Myovant, and Nymox; Dr. Sandhu, receiving advisory board fees, paid to her institution, and grant support from AstraZeneca and Merck Sharp and Dohme, and grant support from Amgen, Endocyte, and Genentech; Dr. Chi, receiving grant support, paid to his institution, and consulting fees from AstraZeneca, Bayer, Astellas, Novartis, Pfizer, Point Biopharma, Roche, and Sanofi, and consulting fees from Daiichi Sankyo, Merck, and Bristol-Myers Squibb; Dr. Sartor, receiving grant support and consulting fees from AAA Pharma, AstraZeneca, Bayer, Endocyte, Progenics, Novartis, and Janssen, consulting fees from Astellas, Blue Earth Diagnostics, EMD Serono, Pfizer, Constellation, Dendreon, Bristol-Myers Squibb, Bravarin Nordic, Clovis, Myriad, Nora Therapeutics, Noxopharm, Point Biopharm, Tenebio, Theragnostics, Telix, Clarity Pharmaceuticals, Celgene, and Fusion, grant support, consulting fees, and fees for expert testimony from Sanofi, and grant support from Invitae, Merck, Innocrin, and Sotio, and serving as co-chairman of GU committee for NRG Oncology; Dr. Agarwal, receiving grant support, paid to his institution, and consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, and Seattle Genetics, grant support, paid to his institution, from Bavarian Nordic, Calithera, Celldex, GlaxoSmithKline, Immunomedics, Medivation, New Link Genetics, Prometheus, Rexahn, Roche, Sanofi, Takeda, and Tracon, and consulting fees from Astellas, Foundation Medicine, and Pharmacyclics; Dr. Olmos, receiving grant support, advisory board fees, lecture fees, and travel support from AstraZeneca, grant support and travel support from Astellas, steering committee fees, advisory board fees, and lecture fees, paid to his institution, travel support, and grant support from Janssen, advisory board fees from Clovis and Daiichi-Sankyo, advisory board fees and lecture fees, paid to his institution, travel support, and grant support from Bayer, travel support from Genentech, F. Hoffman–La Roche, and IPSEN, and advisory board fees and lecture fees, paid to his institution, from Merck Sharp and Dohme, and serving on an advisory board for BioOncotech; Dr. Thiery-Vuillemin, receiving lecture fees and advisory board fees from Ipsen, consulting fees, lecture fees, and advisory board fees from Novartis, Sanofi-Aventis, and Astellas, consulting fees, lecture fees, advisory board fees, and travel support from Bristol-Myers Squibb and Janssen, consulting fees and travel support from F. Hoffmann–La Roche and Merck Sharp and Dohme, grant support, consulting fees, lecture fees, advisory board fees, and travel support from Pfizer, advisory board fees from Bayer, and consulting fees, advisory board fees, and travel support form AstraZeneca; Dr. Roubaud, receiving consulting fees and travel support from Astellas, Ipsen, Sanofi, and Janssen and consulting fees from AstraZeneca; Dr. Özgüroğlu, receiving lecture fees and travel support from AstraZeneca, advisory board fees, lecture fees, and travel support from Janssen, advisory board fees from Sanofi and Roche, advisory board fees and lecture fees from Astellas, lecture fees from Novartis, and travel support from Bristol-Myers Squibb; Dr. Kang, being employed by and owning stock in AstraZeneca; Dr. Burgents, being employed by and owning stock in Merck and being previously employed by AstraZeneca; Drs. Corcoran and Adelman, being employed by and owning shares in AstraZeneca; and Dr. de Bono, receiving grant support, paid to his institution, advisory board fees, consulting fees, lecture fees, and travel support from AstraZeneca, grant support, paid to his institution, advisory board fees, and travel support from GlaxoSmithKline, Pfizer, Taiho, Daiichi Sankyo, Bayer, Orion, Genentech/Roche, Merck Serono, Sierra Oncology, Merck Sharp and Dohme, Astellas, Cellcentric, Sanofi Aventis, and Vertex Pharmaceuticals, and advisory board fees and travel support from Terumo, Menarini/Silicon Biosystems, Bioxcel Therapeutics, Eisai, and Qiagen, and holding patent WO 2005 053662 on DNA damage repair inhibitors for treatment of cancer, licensed to AstraZeneca, and patent US5604213 on 17-substituted steroids useful in cancer treatment, licensed to Janssen. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on September 20, 2020, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the patients who participated in the PROfound trial, their families, and our coinvestigators; Christian H. Poehlein, M.D., of Merck Sharp and Dohme for his contribution to the analysis and interpretation of the data; Allison Allen, Ph.D., of Global Medicines Development at AstraZeneca for her role as the trial medical scientist; Caroline Sibilla, Ph.D., of Precision Medicine and Biosamples, AstraZeneca, for her contribution to enable delivery of diagnostic test results in the trial; Alessandro Galbiati, Ph.D., Kunzah Jamal, Ph.D., and Elisabetta Leo, Ph.D., of the AstraZeneca preclinical team for providing the data on PPP2R2A; and Jacqueline Kolston, Ph.D., and Debbi Gorman, Ph.D., of Mudskipper Business for medical writing assistance with an earlier version of the manuscript.

New England Journal of Medicine 383(24):p 2345-2357, December 10, 2020. | DOI: 10.1056/NEJMoa2022485

ABSTRACT

BACKGROUND

We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.

METHODS

In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.

RESULTS

The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P=0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.

CONCLUSIONS

Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)