Olaparib prolongs overall survival compared with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) and gene alterations in BRCA1, BRCA2, or ATM, according to the final survival analysis of the phase 3 PROfound trial. These results were presented yesterday at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and simultaneously published in the New England Journal of Medicine.
"Metastatic castration-resistant prostate cancer remains lethal," write the investigators in their New England Journal of Medicine publication, led by first author Maha Hussain, MD, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University Feinberg School of Medicine. "Men with deleterious alterations in genes involved in homologous recombination repair, such as BRCA1 and BRCA2, have more aggressive disease and higher mortality than those with proficient homologous recombination repair. The goal of treatment is to prolong survival while maintaining or improving quality of life."
For the open-label PROfound trial, 387 patients with homologous recombination repair (HRR)-deficient mCRPC were randomized in a 2:1 ratio to receive olaparib or a control therapy, consisting of the physician's choice of enzalutamide or abiraterone/prednisone. Patients were divided into two cohorts: cohort A, which included 245 patients with at least one alteration in BRCA1, BRCA2, or ATM; and cohort B, which included 142 patients with at least one HRR alteration in any of the other 12 prespecified genes. For patients who met certain criteria, crossover to olaparib was permitted after imaging-based disease progression. Previously, the investigators reported that olaparib, a poly(adenosine phosphate–ribose) polymerase (PARP) inhibitor, met the trial's primary end point of prolonging progression-free survival compared with enzalutamide or abiraterone/prednisone. Now, the investigators report on their final analysis of overall survival.
In cohort A, olaparib produced a median overall survival of 19.1 months, compared with 14.7 months for enzalutamide or abiraterone/prednisone. In cohort B, olaparib produced a median overall survival of 14.1 months, compared with 11.5 months for enzalutamide or abiraterone/prednisone, a difference that did not meet statistical significance (hazard ratio for death of 0.96, with a 95% confidence interval of 0.63 to 1.49). In the overall study population, median overall survival was 17.3 months for olaparib versus 14.0 months for the control therapy, showing a trend towards improvement that did not quite meet statistical significance (hazard ratio of 0.79, with a 95% confidence interval of 0.61 to 1.03 and a nominal P value of 0.0515). Eighty-six of 131 patients (66%) in the control arm crossed over to receive olaparib.
"PROfound is the first phase 3 trial to show a PARP inhibitor benefit in alpha-controlled overall survival analyses," conclude the investigators in their ESMO Virtual Congress abstract, led by Johann de Bono, MBChB, FRCP, MSc, PhD, FMedSci, Regius Professor of Cancer Research at the Institute of Cancer Research, London, United Kingdom. "Despite extensive crossover from the control arm, olaparib conferred a statistically significant and clinically meaningful prolongation of overall survival versus sequential therapy with enzalutamide or abiraterone in men with mCRPC with progression on prior therapy and alterations in BRCA1, BRCA2 or ATM, with a 31% reduction in the risk for death."
For More Information
Do Bono JS, Mateo J, Fizazi K, et al (2020). Final overall survival (OS) analysis of PROfound: olaparib vs physician's choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations. Ann Oncol (ESMO Virtual Congress Abstracts), 31 (suppl_4):S507-S549. Abstract 610O. DOI:10.1016/annonc/annonc275
Image credit: National Institutes of Health