Dr. Shore on the efficacy of olaparib plus abiraterone in HRR+ mCRPC


“The patients with CDK12, the combination had a PSA50 of about 83% compared to the ABI/placebo of about only 62%,” says Neal D. Shore, MD.

In this video, Neal D. Shore, MD, shares the key findings from the study, “Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial,” which was presented at the 2024 ASCO Genitourinary Cancers Symposium in San Francisco, California. Shore is the US chief medical officer of urology/surgical oncology at GenesisCare USA, as well as the director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Video Transcript:

We looked at a gene-by-gene analysis. When we started PROpel (NCT03732820), we had a 14 gene alteration HRR, homologous recombinant repair, mutation panel. That was based on PROfound (NCT02987543). So, 14 genes which had been approved by FDA, and we broke it down. In the all-comers, almost 30% had an HRR mutation. The most common HRR mutations were BRCA2 and BRCA1. BRCA2/BRCA1 ratio [was] about 90% [to] 10%. ATM was very common, as was CDK12. We looked at the prevalence of other less prevalent gene alterations, which included PALB2, RAD54L, FANCL, BARD1, BRIP1, [and] RAD51B. These are much less common.

When we looked at the 3 most common gene alterations, we looked at not only the rPFS benefit, but the OS benefit, and we showed this in sub-analyses and a forest plot that was part of our poster. First and foremost, in all patients, as I said, PROpel showed an rPFS benefit across the board, which was clearly statistically significant. Thus, we met the primary end point of the study. As it related to overall survival, with our data cutoff of overall survival, our third analysis, there was also a greater than 7-month benefit. When we break it down to the BRCA mutations, the BRCA2 and BRCA1, as well as the ATM and the CDK12, when we look at these single gene alterations, we see, clearly in the BRCA, undoubtedly positive findings on rPFS and OS. That's in the poster, and clearly trending positively for the combination olaparib with abiraterone vs abiraterone acetate, prednisone, plus placebo, clearly demonstrating a trending benefit for those 3 predominant genes in our totality of the pool, or the 30% of our HRR positive mutations. Remember, 70% of our patients did not have mutations, and yet the PROpel study was still successful on the primary end point of rPFS. When we looked at a lot of the single genes, such as CHEK2, PALB2, RADs, [and] FANCL, they're very small prevalence, so we really couldn't come up with any significant conclusions.

Another really important demonstration in the study, when we looked at the BRCA patients, and we looked for example at the PSA50 responses, greater than 93% for those patients with BRCA vs 41% in the ABI/placebo. For the patients with ATM, upwards of 70% PSA50. The patients with CDK12, the combination had a PSA50 of about 83% compared to the ABI/placebo of about only 62%. So, it's always important. One of the things that many of us have said was we'd love to be able to combine meta-analyses of other studies that have used comparable gene profiles of these mutations [where] the prevalences are very small to try to see if we can come up with some additive conclusions.

This transcription has been edited for clarity.

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