BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points. RESULTS: At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea. CONCLUSIONS: At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)

Ashford Cancer Centre Research Adelaide South Australia

Carolina Urologic Research Center Myrtle Beach SC

Centre Hospitalier de l'Universite de Montreal Montreal

Centre Hospitalier Intercommunal de Cornouaille Quimper France

Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz Besançon France

Centro de Investigaciones Clinicas Viña del Mar Valparaíso Chile

Duke Cancer Institute Center for Prostate and Urologic Cancer Duke University Durham NC

Fondazione Istituto Nazionale Tumori Milano Milan

Global Medicines Development Oncology R and D AstraZeneca Cambridge United Kingdom

Global Medicines Development Oncology R and D AstraZeneca Gaithersburg MD

Hospital de Base São José do Rio Preto São José do Rio Preto Brazil

Hospital Nossa Senhora da Conceição Porte Alegre Brazil

Hospital Universitario Virgen Macarena Seville Spain

Izmir Economy University Medical Park Hospital Karsiyaka Turkey

Kagawa University Hospital Kagawa Japan

Kaiser Permanente Southern California Los Angeles

Keio University School of Medicine Tokyo

Masaryk Memorial Cancer Institute Brno Czech Republic

Merck and Co Inc Rahway NJ

National Cancer Center Goyang South Korea

Radboud Universitair Medisch Centrum Nijmegen Netherlands

Sunnybrook Research Institute and Odette Cancer Centre Toronto

The Christie and Salford Royal Hospital NHS Foundation Trusts University of Manchester Manchester United Kingdom

Translational Medicine Oncology R and D AstraZeneca Cambridge United Kingdom

University Hospital Southampton Southampton United Kingdom

References provided by Crossref.org

Toxicities of PARP inhibitors in genitourinary cancers

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ClinicalTrials.gov
NCT03732820