Olaparib Plus Abiraterone Improves rPFS Across Biomarker Groups for mCRPC


Fred Saad, MD, FRSC, discusses the findings of a biomarker analysis of the PROpel trial in patients with metastatic castration-resistant prostate cancer.

Fred Saad, MD, FRSC, director of prostate cancer research at Montreal Cancer Institute, discusses the findings of a biomarker analysis of the PROpel trial (NCT03732820) in patients with metastatic castration-resistant prostate cancer (mCRPC).

The phase 3 PROpel trial investigated the combination of olaparib (Lynparza) plus abiraterone versus abiraterone plus placebo in 796 patients with mCRPC. At the primary analysis, olaparib showed a median radiographic progression-free survival (rPFS) of 24.8 months compared with 16.6 months with placebo (HR, 0.66; 95% CI, 0.54-0.81; P < .0001). An interim analysis as of March 2022 showed an rPFS of 25.0 months for olaparib versus 16.4 months for placebo (HR, 0.67; 95% CI, 0.56-0.81).

According to Saad, the biomarker analysis evaluated patients with homologous-recombination repair (HRR) mutations, non-HRR mutations, BRCA mutations, and without BRCA mutations. Using tissue and circulating tumor DNA (ctDNA), about 98% of patients were able to have their mutational status assessed.

All biomarker subgroups showed improvement of at least 5 months in rPFS. Those with BRCA mutations showed significant benefit, but based on blinded independent central review, patients without BRCA mutations also showed an 11-month improvement in rPFS with olaparib (27.6 months versus 16.6 months; HR, 0.72; 95% CI, 0.58-0.90). Saad says this is an opportunity to improve outcomes in the first line, keeping in mind that patients may not receive subsequent therapy and median overall survival is about 3 years for mCRPC.


0:08 | The biomarker analysis was done, it was preplanned, all patients coming in could get on to the study regardless of their biomarker status, but all had to contribute tissue and blood for ctDNA. It was done based on FDA-standardized approaches with FoundationOne. As expected, about 30% of patients had tissue that was not informative. That's why it was important to have the ctDNA. By combining tissue and ctDNA, we had about 98% of patients where we could classify them as having detectable or no detectable mutation, and only 2% without. That was very important and allowed us to look deeper into the biomarker analysis, including BRCA mutation, or non-BRCA mutation.

1:00 | Clearly, the patients [who] looked like they're getting the most benefit are the BRCA-mutated patients, but again, even the non–BRCA-mutated patients were getting the prolonged rPFS benefit. Based on blinded independent review, it was actually an 11-month improvement in rPFS in the patients that had no BRCA mutation detected.

1:23 | I think the only thing to highlight from the results [is that this is an opportunity] to do better than what we are able to do today in patients [who] are treated for first-line mCRPC. In 16 to 18 months, patients will have radiographic progression, and will have to go on to subsequent therapy that many don't get. Survivals are still under 3 years in first-line mCRPC.

Clearly, this is an opportunity to make a bigger difference in the lives of patients that are diagnosed with first-line mCRPC that have not yet been exposed to a novel hormonal therapy.

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