Olaparib/Abiraterone Shows rPFS Benefit in mCRPC Regardless of HRR Status

Alicia K. Morgans, MD, MPH

Associate Professor of Medicine

Feinberg School of Medicine

Northwestern University

Chicago, IL

Targeted Oncology: What is the significance of the phase 3 PROpel trial (NCT03732820) of olaparib (Lynparza) plus abiraterone acetate (Zytiga) for metastatic castration-resistant prostate cancer (mCRPC)?

ALICIA K. MORGANS, MD, MPH: This [combination] is moving from later-stage mCRPC up into the first line of mCRPC. The PROpel study included patients who had potentially had docetaxel [Taxotere] in the metastatic hormone-sensitive setting, no prior treatment with abiraterone, and no exposure for most of the patients to any of the other novel intensive hormonal agents. Patients were essentially those with first-line mCRPC, and they were randomly assigned to treatment with abiraterone, which is a standard of care in first-line mCRPC, with or without olaparib. This was an all-comers patient population.

After enrollment, before data analysis, they did assess patients for their germline and somatic alterations to try to understand that, but that was not known at the time of randomization. The primary end point here was radiographic progression-free survival [rPFS] in the overall all-comer population, with overall survival (OS) being the key secondary end point, and then of course they did look at patients by the HRR [homologous recombination repair] alteration status.

The baseline characteristics showed that just under 30% of patients had an HRR alteration.¹ The teams used tissue to try to understand the HRR status and then also did circulating tumor DNA test as a backup, but for about 2% of patients they couldn’t. This was a pretty [fit] group, with the majority of patients having an ECOG performances status of 0 and most of these patients were not symptomatic. Only about 20% of patients had exposure to docetaxel in the hormone-sensitive setting.

For investigator-assessed rPFS, the combination of olaparib and abiraterone had a 34% reduction in the risk of progression or death than abiraterone alone. Abiraterone is the standard of care in this setting. This is an incredibly effective first-line treatment for mCRPC in a population that did not get prior AR exposure. To benefit on top of that is interesting to me and it’s also interesting that this is an all-comers population, so it includes people with HRR mutations and without. The HR was 0.66 [95% CI, 0.54-0.81; P < .0001].

What are the most recent updates to these results?

We saw at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium [ASCO GU] that this was updated and it continues to show this benefit with an HR that holds at 0.66.²

Those patients who did have the HRR mutations have a significantly improved rPFS. Even those patients who were negative for HRR had a significant improvement in rPFS. [This is] just an interesting piece of the data here, a subgroup analysis not powered for this. Patients with BRCA2 mutation have a way bigger benefit than patients who had an HRR mutation but were not BRCA1 and BRCA2.

OS was a temporally driven end point, so the investigators said that at these time points we’re going to get these analyses, and the final OS analysis by time [were presented at ASCO GU]. But it didn’t have enough events to…meet the power needed to answer this question.

The HR for OS in the all-comers population is trending in the right direction, but the P value is not statistically significant because they did so many looks at the data [HR, 0.81; 95% CI, 0.67-1.00; P = .0544]. You would need to have a lot more zeros in there to reach statistical significance. They are going to do another analysis.

But if we look at the median OS between these 2 arms, 42 months for the all-comers population in the combination versus 34 months for the abiraterone alone, [it is a] highly effective first-line treatment for mCRPC. That’s a big numerical difference, [though] not quite statistically significant.

Which types of patients benefited most? Did those without HRR mutations benefit?

In the non-HRR patients, in the abiraterone/olaparib group, there’s about a 3.5 month improvement, [which is] not statistically significant in OS. There’s a possibility that these are equivalent, but it’s numerically separating and that’s difficult to understand why that’s happening in a group that should not have any benefit at all from PARP inhibitors as far as we know. It’s interesting that there is at least this rPFS that’s statistically significant even in the non-HRR mutation [population]. The all-comers data is being pulled by the BRCA2 and the HRR. But, when we look only at the non-HRR, there’s still a statistically significant improvement in rPFS and it’s difficult to sort.

What stood out in regard to safety and tolerability of the combination on this trial?

The adverse events suggest that there are not any new safety signals.¹ Cytopenias still are an issue with PARP inhibitors, [as well as] fatigue and some gastrointestinal [toxicities]. They also noted incidental pulmonary embolisms were numerically greater in patients getting the combination. If this becomes a combination that we use in the clinic, we are going to have to be careful and note when our patients have lower extremity swelling or shortness of breath. We have to look for deep vein thrombosis and pulmonary embolism. It was a numerical difference, did not seem statistically significant, but it is something for all of us clinicians to keep an eye on.

_References:

_{1. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043}

_{2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl_6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16}