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•In this phase III study, 387 patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA repair gene defects who progressed on abiraterone or enzalutamide were randomized in a 2:1 ratio to olaparib (PARP inhibitor) or physician's choice of enzalutamide or abiraterone. Patients in cohort A had at least one alteration in BRCA1, BRCA2, or ATM; those in cohort B had alterations in any of 12 other prespecified genes. The primary endpoint was imaging-based progression-free survival (PFS) in cohort A. In cohort A, olaparib was associated with significantly longer imaging-based PFS (HR, 0.34; P < .01), higher objective response rate, and longer time to pain progression compared with the control group.
•This is a very important and practice-changing study because it's the first phase III trial showing superiority of a PARP inhibitor for patients with mCRPC and DNA repair gene alterations, validating the importance of biomarker testing for men with metastatic disease. In addition, this study met the overall survival endpoint for olaparib (data now shown; press release, April 2020).
– Pedro C. Barata, MD
BACKGROUND
Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.
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 end points than either enzalutamide or abiraterone.
The New England Journal of Medicine
Olaparib for Metastatic Castration-Resistant Prostate Cancer
N. Engl. J. Med 2020 Apr 28;[EPub Ahead of Print], J de Bono, J Mateo, K Fizazi, e
PARP inhibitor Olaparib, phase 3 study findings (PROpel)
enzalutamide (XTANDI®, Astellas Pharma Inc.) for patients with metastatic castration-sensitive prostate cancer (mCSPC). 
