Fred Saad, MD, Centre Hospitalier de l’Université de Montréal, Montréal, Canada, shares updated results from a biomarker analysis in the phase 3 PROpel trial, which is evaluating abiraterone plus olaparib vs abiraterone plus placebo for patients with metastatic castration-resistant prostate cancer.

The analysis showed that all assessed biomarker subgroups, including patients with non-homologous recombination repair (HRR) mutations, HRR mutations, and BRCA mutations, abiraterone plus olaparib meaningfully improved the radiographic progression-free survival (PFS), compared to abiraterone plus placebo.

These results were presented at the 2022 European Society of Medical Oncology (ESMO) Congress.

Transcript:

Hi, I'm Fred Saad, professor and chairman of urology at the University of Montreal Hospital Center and director of genitourinary oncology. It's my pleasure to summarize some data that I presented today at ESMO 2022 here in Paris.

I summarized the PROpel phase 3 study that we presented and published initially at the first interim analysis, looking at patients in first-line metastatic castration-resistant prostate cancer (mCRPC) who are allowed to have had chemotherapy in the hormone-sensitive prostate cancer (HSPC) setting. Patients were randomized 1:1 to get olaparib plus abiraterone, versus abiraterone plus placebo in the first-line mCRPC setting. About 800 patients were randomized. The primary endpoint was investigator-determined rPFS, or radiographic progression-free survival. We all also had blinded central review for all of these analyses. Secondary endpoints included overall survival, and multiple other secondary endpoints that were important, including safety.

The updated analysis that I presented at ESMO shows that we continue to see improvements in radiographic progression-free survival, now at 8.6 months. I also presented data on biomarker analyses, that hasn't previously been published or reported. We did analysis of biomarker status based on [homologous recombination repair] HRR mutations in all patients, since all patients submitted tissue and ctDNA, and that's how we determined status. It was pre-planned but wasn't a randomized stratification. 70% of patients did not harbor detectable mutations and 30% harbored detectable mutations. And as expected, about 10% of patients harbor BRCA mutations.

The results show that in patients with or without mutations, there is an advantage in radiographic progression-free survival with the combination of abiraterone and olaparib, compared to abiraterone alone. This was significant in terms of a hazard ratio of 0.76 for those without mutations and of 0.5 for those with mutations, and both are below 1 in terms of confidence intervals. In terms of BRCA mutations, specifically, the hazard ratio for the BRCA-mutated patients was very significant, with a hazard ratio of 0.23. And in the patients without BRCA mutations, again, more than a 5-month improvement in radiographic progression-free survival, and a hazard ratio 0.76 and a confidence intervals below 1. Based on blinded independent control analysis, there was actually an 11-month improvement in rPFS in patients that did not harbor BRCA mutations.

Importantly, we also updated overall survival. At the initial analysis, we had 28% of deaths and we saw a trend towards an improvement in overall survival. Now, at this second interim analysis, we have 40% of death, and patients continue to show improvements in overall survival now with a hazard ratio of 0.83 and a P-value of 0.11. So really heading in the right direction, and as expected, because the control arm is a life-prolonging control arm, this separation of the curves is occurring after 22 months.

We hope to have the final analysis soon, but it's already very impressive with the small size of the study, that we're already seeing this difference in the intent-to-treat group of patients with or without mutations. And lastly, this long-term analysis shows that there isn't an increased toxicity or adverse events as patients stay on the drug for a longer period of time, which is very reassuring.

Overall, hopefully this will be the first combination in mCRPC to be approved and used in the clinic, for patients that we feel are appropriate to be treated with more intensive therapy, which is much needed for patients who are, unfortunately, destined to die of metastatic prostate cancer.

Source:

Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. Biomarker analysis and updated results from the Phase III PROpel trial of abiraterone (abi) and olaparib (ola) vs abi and placebo (pbo) as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).” Presented at ESMO Congress; September 9-13, 2022; Paris, France. Abstract 1357O.