Methods: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review.
Results: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib.
Conclusions: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported endpoints than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.)
Authors: J. de Bono, J. Mateo, K. Fizazi, F. Saad, N. Shore, S. Sandhu, K.N. Chi, O. Sartor, N. Agarwal, D. Olmos, A. Thiery-Vuillemin, P. Twardowski, N. Mehra, C. Goessl, J. Kang, J. Burgents, W. Wu, A. Kohlmann, C.A. Adelman, and M. Hussain
Citation: Johann de Bono, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi, et al. “Olaparib for Metastatic Castration-Resistant Prostate Cancer.” New England Journal of Medicine, April 28, 2020. https://doi.org/10.1056/NEJMoa1911440.
Listen: PROfound Study - PARP-inhibitor Olaparib in Advanced Prostate Cancer Patients with Specific Tumor Mutations - Maha Hussain