Longer overall survival for castration-resistant metastatic prostate ca

In men whose castration-resistant, metastatic prostate cancer is characterized by BRCA1, BRCA 2 or ATM mutations, olaparib appears to offer long term, durable benefits compared to treatment with enzalutamide or abiraterone plus prednisone, investigators with the PROfound trial report.

The benefit of olaparib was previously reported, but Maha Hussain,MD of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago reported the final analysis of PROfound at the European Society of Clinical Oncology (ESMO) virtual congress and also published their findings in The New England Journal of Medicine.

“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,” they wrote.

The phase III trial was open-label, and 256 patients were randomly assigned to olaparib (300 mg twice daily) and 131 patients were assigned to the control group. Control group patients received either enzalutamide (160 mg once daily) or abiraterone (1000 mg once daily) plus prednisone (5 mg twice daily) by physician’s choice.

The final analysis by Hussain, et al reported results from Cohort A (n=245), which included patients with at least one BRCA 1, BRCA 2, or ATM alteration and cohort B (n=142) of patients with “at least one alteration in any of other 12 prespecified genes.”

Cohort A final analysis results:

  • 148 of 245 patients (60%) had died.
  • Median overall survival was 19.1 months with olaparib and 14.7 months for controls P =0.02.
  • Crossover adjusted (control to olaparib) sensitivity analysis HR 0.42, CI 0.19-0.91).

Cohort B final analysis results:

  • 100 of 142 patients had died.
  • Median overall survival was 14.1 months with olaparib and 11.5 months with control therapy (HR 0.96, 95% CI 0.63-1.49).
  • Crossover adjusted (control to olaparib) HR was 0.83 (95% Ci 0.11-5.98).

“After the death of 248 of 387 patients (64%) in the overall population (cohorts A and B), the median duration of overall survival was 17.3 months with olaparib and 14.0 months with control therapy (hazard ratio for death, 0.79; 95% CI, 0.61-1.03). After adjustment for crossover from control therapy to olaparib, the hazard ratio was 0.55 (95% CI, 0.29-1.06),” Hussain and colleagues wrote.

The authors noted that the “risk of death was 31% lower with olaparib than with control therapy, despite substantial crossover from control therapy to olaparib.”

Of note, when the PROfound trial was proposed, there was scant evidence to “validate the efficacy of switching from one next-generation hormonal therapy directed at androgen signaling to another” although that approach was “commonly applied in clinical practice. Small clinical studies that assessed sequential next-generation hormonal therapy had shown some antitumor activity, and because patients with disease progression had restricted options for systemic treatment, this approach was incorporated into clinical guidelines and adopted as a standard of care,” they wrote. “With the caveat that cross-trial comparisons should be considered with caution, we note that recently reported data from the CARD trial have shown that the efficacy of cabazitaxel was superior to that of a second androgen-signaling–directed, next-generation hormonal agent in patients (not selected on the basis of biomarkers) who had previously been treated with docetaxel and whose disease had progressed during 12 months of previous treatment with a next-generation hormonal agent. However, data to guide treatment sequencing for patients with metastatic castration-resistant prostate cancer and homologous recombination deficiency remain sparse outside of that trial. In addition, cabazitaxel was not considered to be an appropriate choice for the control treatment in the PROfound trial, because it is only approved for use after docetaxel, and patients were included in our trial regardless of previous receipt of chemotherapy.”

  1. Note that the benefit of olaparib appears to be confined to castration-resistant prostate cancers with alterations in BRCA1, BRCA2 or ATM genes.

  2. Be aware that there was significant crossover from the control arm to olaparib arm in this trial.

Peggy Peck, Editor-in-Chief, BreakingMED™

The PROfound trial was supported by AstraZeneca.

Hussain reported grants from AstraZeneca, during the conduct of the study; grants, personal fees and non-financial support from Pfizer, grants and personal fees from AstraZeneca, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Genentech/Roche, personal fees and non-financial support from Astellas Pharma, personal fees from Physicians’ Education Resource, personal fees from Projects in Knowledge, personal fees from Sanofi/Genzyme, personal fees from Research to Practice, personal fees from BMS, personal fees from Daiichi Sankyo, outside the submitted work; In addition, Hussain has a patent SYSTEMS AND METHODS FOR TISSUE IMAGING issued, a patent METHOD OF TREATING CANCER issued, and a patent Dual Inhibition of MET and VEGF for the treatment of castration resistant prostate cancer and osteoblastic bone metastases issued.

Cat ID: 25

Topic ID: 78,25,25,697,935,192,73,925,696