The results of recent trials of PARP (poly [ADP-ribose] polymerase) inhibitor plus second-generation androgen receptor inhibitor combinations have had varying results in metastatic castration-resistant prostate cancer. Some trials suggest the benefit is confined to those with BRCA mutations and/or homologous recombination repair (HRR) mutations, and others—such as PROpel—indicate this combination may be beneficial in all patients.
Oliver Sartor, MD
Commenting on the totality of data, including those from PROpel, Oliver Sartor, MD, said: “I think it’s clear that in patients with BRCA mutations, olaparib plus abiraterone is a home run. This is an extremely active and important combination [in this subgroup of patients].” Dr. Sartor is Assistant Dean for Oncology and the C.E. and Bernadine Laborde Professor of Cancer Research, Medicine, and Urology Departments, Tulane University School of Medicine, New Orleans.
The data are less clear-cut in other subgroups. “In terms of patients with non-BRCA, HRR-mutated disease, the case is borderline. In my practice, I would use this combination preferentially in those in whom PARP inhibition would have a major effect—patients with BRCA1 and BRCA2 mutations. There is also evidence of efficacy in those with PALB2 mutations,” he said.
Dr. Sartor continued: “There have been three different trials looking at this type of combination—PARP inhibitor plus second-generation androgen receptor inhibitors niraparib, olaparib, and talazoparib, respectively. At the 2023 ASCO GU Cancers Symposium, Dr. Clarke presented updated survival from PROpel. Although the benefit of the combination of olaparib/abiraterone in patients with BRCA-mutated disease is clear, if you take out those with BRCA-mutated disease, it looks like the non-HRR–mutated and HRR-mutated non-BRCA subgroups have a similar outcome. The trend for investigator-assessed radiographic progression-free survival is the same in both subgroups,” he noted.
Words of Caution
Dr. Sartor took issue with the survival analysis. “The trend toward overall survival was not well broken out according to non-BRCA status. We really have a win for the BRCA patients, as shown in PROpel. For the non-BRCA patients, it would be my preference to use precision medicine and not treat everyone [with this combination] because of the side effects and cost,” he stated.
“It matters what the FDA says, and they have said that they need to review more data before the combination is approved. The final preplanned survival analysis has just 47% of the events, so fewer than half of the patients have died so far, and this is reportedly the final analysis. I took umbrage at that. Longer follow-up is needed for the BRCA and non-BRCA subgroups. It is conjecture whether the survival curves will be different over time,” Dr. Sartor said.
“Another concern is longer-term safety with PARP inhibitors. In my opinion, we need longer experience to see whether there are long-term alterations in bone marrow with longer exposure to PARP inhibitors,” he stated.
DISCLOSURE: Dr. Sartor has stock or other ownership interests with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Clovis Oncology, GlaxoSmithKline, Eli Lilly, Noria Therapeutics, PSMA Therapeutics, and United Health Group; has served as a consultant or advisor to Advanced Accelerator Applications, ART BioScience, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis Oncology, Constellation Pharmaceuticals, Dendreon, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Myovant Sciences, Myriad Genetics, Noria Therapeutics, Novartis, Noxopharm, Pfizer, Point Biopharma, Progenics Pharmaceuticals, Ratio, Sanofi, Telix Pharmaceuticals, TeneoBio, and Theragnostics; has received institutional research funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation Pharmaceuticals, Dendreon, Endocyte, InVitae, Janssen, Lantheus, Merck, Progenics, Sanofi, and SOTIO Biotech; has patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (U.S. patent awarded January 23, 2007; patent no. 7,166,691); has provided expert testimony for Sanofi; and has received reimbursement for travel, accommodations, or expenses from AstraZeneca, Bayer, Johnson & Johnson, Progenics, and Sanofi.
