Clinical Pearls & Morning Reports
Published December 9, 2020
The PROfound trial enrolled patients with metastatic castration-resistant prostate cancer who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in homologous recombination repair and whose disease had progressed during previous treatment with a next-generation hormonal agent. Read the NEJM Original Article here.
Q: Define cohorts A and B in the PROfound trial.
A: The overall population comprised patients who had at least one alteration in BRCA1, BRCA2, or ATM (cohort A) and patients with at least one alteration in any of the other 12 prespecified genes — BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L (cohort B).
Q: What were the previously published results for cohort A of the PROfound trial?
A: In cohort A, the patients who received olaparib had a significantly longer duration of imaging-based progression-free survival than those who received the physician’s choice of enzalutamide or abiraterone plus prednisone (control). Benefits with olaparib were also shown with respect to the key secondary end points of confirmed objective response rate and time to pain progression in cohort A (longer with olaparib than control).
A: In this analysis of overall survival among patients 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, olaparib led to significantly longer overall survival than enzalutamide or abiraterone plus prednisone. This improvement was noted despite substantial crossover from control therapy to olaparib. The trial was not designed to test the benefit of therapy with respect to overall survival at the individual gene level. However, a clinical benefit was not observed for olaparib in the population of patients who had other homologous recombination repair gene alterations.
A: No new safety signals were observed after the longer follow-up, as compared with the follow-up period in the primary analysis. The most common adverse events among the patients in the olaparib group and those who crossed over to receive olaparib were anemia, nausea, and fatigue or asthenia; among those in the control group, the most common adverse events were anemia, fatigue or asthenia, and decreased appetite. Adverse events that were suspected by the site investigators to be causally related to olaparib were most frequently anemia (occurring in 39% of the patients), nausea (in 36%), and fatigue or asthenia (in 32%); olaparib was discontinued because of anemia in 7% of the patients and because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia in 1% of the patients for each.