Frontline Olaparib/Abiraterone Effective in mCRPC Biomarker Subgroups

Fred Saad, MD

A significantly prolonged radiographic progression-free survival (rPFS) and trend toward overall survival (OS) improvement displayed in the phase 3 PROpel trial (NCT03732820) led investigators to question whether patients with frontline metastatic castration resistant prostate cancer (mCRPC) and certain biomarkers would still derive benefit.¹

The combination of olaparib (Lynparza) and abiraterone achieved a median rPFS of 24.8 months compared with 16.6 months with placebo (HR 0.66; 95% CI, 0.54-0.81; P < .0001). The OS, which had reached 28.6% maturity, favored the olaparib/abiraterone arm vs placebo (HR 0.86; 95% CI, 0.66–1.12).²

A biomarker analysis was conducted to determine whether rPFS and OS would be similar in key biomarker subgroups. Utilizing the FoundationOne®Liquid CDx, tumor tissue was collected from all patients to assess their homologous recombination repair (HRR) mutational status. The groups evaluated were patients with non-HRR mutations, patients with HRR mutations, patients with non-BRCA mutations, and patients with BRCA mutations.

Results showed that the combination of olaparib and abiraterone achieved a meaningful improvement in rPFS compared with placebo and abiraterone in all biomarker groups assessed. Moreover, the safety and tolerability of olaparib/abiraterone was maintained.

In an interview with Targeted Oncology™, Fred Saad, MD, FRSC, director of prostate cancer research at Montreal Cancer Institute/CRCHUM, discussed key biomarkers for prostate cancer and findings from the PROpel biomarker analysis.

TARGETED ONCOLOGY: What are the key biomarkers to test for in patients with metastatic castration-resistant prostate cancer?

Saad: The important biomarker to test for is PSA [prostate specific antigen]. Patients who are on ADT [androgen deprivation therapy] progressing defines metastatic castration resistant prostate cancer. That's the most important biomarker, to identify patients who have become metastatic castration resistant. The main criteria to get in to the PROpel study were to be metastatic castration resistant, and be progressing, at least PSA-wise, with or without radiographic progression at the time of study entry. Other biomarkers that are of interest are when we're using a PARP inhibitor, HRR mutations. This includes looking at BRCA mutations, ATM, or all the other list of HRR mutations are important but were not included in entrance criteria for the PROpel study.

Can you briefly recap the primary analysis results from PROpel and explain what signals led to the biomarker analysis?

PROpel is a randomized phase 3 placebo-controlled trial that included patients in the first-line mCRPC setting. This was an all-comer population,but all patients contributed tissue and ctDNA [circulating tumor DNA] for biomarker analysis, so we could figure out if some patients were not benefiting or benefiting more than others. Patients came into the study who were randomized 1:1 to getting abiraterone plus or minus olaparib. Even in the control arm there was life-prolonging therapy in the PROpel study.

The primary analysis showed that we were able to significantly delay radiographic progression-free survival or death by over 8 months in the combination arm compared with the standard of care apparatus, which is very similar to what we saw of abiraterone against a placebo in this study that led to the approval of abiraterone. All the subgroups benefited whether they had chemotherapy, visceral metastases, or we detected mutations coming into the study. Clearly. the ones that had mutations appeared to be gaining more benefit than those without mutations. But even those without mutations had hazard ratios of 0.76 and confidence intervals that were below 1. It showed that there is clear benefit, even in that subgroup of patients.

Can you explain the design and methods use of this biomarker analysis?

The biomarker analysis was done in all patients who could get onto 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 who could classify them as having detectable or non-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.

The patients that looked like they're getting the most benefit are the BRCA-mutated patients,but even the nonBRCA-mutated patients were getting the prolonged rPFS benefit. Based on blinded independent review was an 11-month improvement in rPFS in the patients that had no BRCA mutation detected.

Can you explain the results from PROpel that you presented at ESMO?

The only thing to highlight from the results are that this is an opportunity to do better than what we are able to do today in patients with mCRPC treated in the first-line setting. 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.

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. We need to be able to advance the science and offer more to our patients that, unfortunately, are all going to die of prostate cancer.

How do you think this research be useful for making treatment decisions in the future?

We need these kinds of results from phase 3 studies to show that there's a benefit of doing more than the standard of care that we use for mCRPC. I think this is going to lead to change in practice, especially in patients at highest risk. Obviously, patients with biomarker positive disease, like BRCA or other mutations, are the ones that are going to benefit the most immediately. But even those without mutations have the opportunity to benefit and then it's going to be a case-by-case decision.

I think we have an opportunity if we know the biomarker status, age, and a site of metastases, and whether they had chemotherapy. We as physicians don't do everything to everybody. We try to personalize our decisions based on the person in front of us. If we have the biomarkers, great. But unfortunately, it's not easy to get good biomarker status today in many areas around the world. This is an opportunity to do better, and see what we can do if we don't have the opportunity to know the biomarker status.

Olaparib combined with abiraterone, and prednisone or prednisolone is being considered for FDA approval in the United States. What do think the impact of such an approval will be on the field?

If this regimen gets approval, it will be an opportunity to offer more than what we can offer today for these patients that have lethal prostate cancer. The question of how early to give is not answered by this study,but it's clearly answered that these patients will benefit. If started in the first line mCRPC, we know that olaparib is effective if you've already failed a novel hormonal and have a BRCA mutation or an ATM mutation. But that is a very small subgroup. This is an opportunity to treat many more patients earlier, and hopefully make a big difference for those patients destined to unfortunately die of prostate cancer.

REFERENCES:

1. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(6):11-11. doi:10.1200/JCO.2022.40.6_suppl.011

2. Armstrong AJ, Saad F, Thiery-Vuillemin , et al. 1370P Detection of mutations in homologous recombination repair (HRR) genes in tumour tissue (TT) and circulating tumour DNA (ctDNA) from patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) in the phase III PROpel trial. Ann Oncol. 2022;33(7):S1168. doi:10.1016/j.annonc.2022.07.1502