Combination Regimens May Expand PARP Inhibitor Efficacy in mCRPC

PARP inhibitors plus androgen receptor (AR)-targeted therapies may become a new effective treatment approach in patients with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC), although PARP inhibitor monotherapies with olaparib (Lynparza) and rucaparib (Rubraca) remain the current standards in this population, according to Tian Zhang, MD, MHS.

“PARP inhibitors are effective, and we’ve been using them as monotherapy for a while,” Zhang said in an interview with OncLive^® during the 2023 Prost8 Cancer Conference.

In the interview, Zhang discussed the current role of PARP inhibitor monotherapy in mCRPC, conversations regarding early line use of the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy Lutetium 177 (¹⁷⁷Lu) PSMA-617 (¹⁷⁷Lu-PSMA-617; Pluvicto) in refractory castration-resistant prostate cancer (CRPC), and the importance of developing treatment standards that define the prostate cancer populations in which combination therapies may be most effective.

The phase 3 PROfound trial (NCT02987543), which investigated the PARP inhibitor olaparib in patients with HRR-altered mCRPC who had progressed on enzalutamide (Xtandi) or abiraterone acetate (Zytiga), found that olaparib treatment resulted in a median radiographic progression-free survival (rPFS) of 7.4 months vs 3.6 months with enzalutamide or abiraterone in patients with BRCA1, BRCA2, or ATM alterations.¹ Similarly, the phase 3 TRITON3 trial (NCT02975934), which evaluated another PARP inhibitor, rucaparib, in patients with mCRPC who had progressed on an AR pathway inhibitor, showed that rucaparib induced a median rPFS of 11.2 months vs 6.4 months with control in patients with BRCA alterations.² Zhang contextualized these findings with single-agent PARP inhibitors within the landscape of HRR-deficient mCRPC and described how these advances pave the way for combining PARP inhibitors with hormonal therapies.

Zhang is an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center in Dallas, Texas.

OncLive^®: How is PARP inhibitor monotherapy currently used in HRR-deficient mCRPC?

Zhang: We now have 2 approvals [for patients with] mCRPC with alterations in the HRR pathway. PARP inhibitors act in a synthetic lethal way in patients with BRCA loss or other alterations and double-strand break repair.

The 2 trials that have shaped the field of PARP monotherapy are the PROfound trial, in which olaparib was compared against abiraterone or enzalutamide in patients with mCRPC with prior novel hormonal agent exposures, and the TRITON3 trial, which tested rucaparib against the standard of care [SOC]. Interestingly, TRITON3 also allowed the use of chemotherapy, docetaxel, in the control cohort.

PROfound was positive in prolonging rPFS. Therefore, we’ve been using olaparib in that setting for patients with HRR defects. The seminal TRITON3 trial was reported at the 2023 Genitourinary Cancers Symposium, and we saw the important results of the primary analysis of the BRCA-mutated population with rPFS as the primary end point. In that population, we saw a drastically improved rPFS interval for patients treated with a PARP inhibitor vs a SOC. If we break the control cohort into those who received docetaxel vs those who received an AR-targeted agent, it looks like the benefit for a PARP inhibitor over docetaxel is a little less than [the benefit of a PARP inhibitor] compared against patients treated with an AR antagonist. Therefore, the PARP inhibitor was more effective in the select population with HRR defects.

How did this meeting approach the topic of potential combination therapies with PARP inhibitors?

Our discussion primarily focused on the combination of PARP inhibitors with novel hormonal agents and when and how to use those combinations. The monotherapies have accepted use across the board for patients with HRR defects. The TRITON3 data add to our evidence of supporting patients treated with PARP inhibitors vs either chemotherapy or an AR-targeted agent.

Across these populations, we are continuing to use PARP inhibitors as monotherapies. The biggest controversy is whether we should use them in combination with AR-targeted agents. Should we use the combination up front for all patients with CRPC, regardless of HRR status, or should we use them in a select patient population?

The second question is whether the combination of a PARP inhibitor with an AR-targeted therapy is better than sequencing each as monotherapies. When thinking through these questions, often, we’re considering toxicity issues, affordability issues, and whether a patient is appropriate for the underlying AR-targeted agent and then whether they should receive the combination.

What questions did this Prost8 Cancer Conference answer, and what questions require further research and discussion?

From a [trial design] perspective, [both the phase 3 PROpel (NCT03732820) and TALAPRO-2 (NCT03395197) trials] had an agreed-upon primary end point of rPFS in all-comers. These trials fulfilled their primary end points, which were agreed upon by the regulatory agencies.

We all agree that approvals may come [for PARP inhibitor combinations in mCRPC]. We’re not sure which patients to use the combinations for. We’ll know more once the regulatory agencies weigh in and give further guidance about the specific population.

Currently, we have PARP inhibitor monotherapies available. Olaparib is probably used more often than rucaparib, but both have labels in refractory mCRPC. Combination strategies is the area where many of us are grappling with who the right patient is to treat with the combinations, how long to treat them for, and in what population we accept any additional toxicities.

How did this meeting address the topic of treatment sequencing with ¹⁷⁷Lu-PSMA-617?

The conversations around radiopharmaceuticals [such as] ¹⁷⁷Lu-PSMA-617 were important. PSMA-targeted lutetium is approved in refractory CRPC, and many of us are considering using it earlier as we hear results from trials that have [investigated it] in earlier disease settings. We discussed how many cycles we absolutely need for those patients and how we can potentially adapt their treatment to their responses.

There was also a great conversation about SPECT-CT imaging as an indicator for assessing response and a biomarker for how the lutetium is taken up. I’m looking forward to seeing the new data that are coming out for lutetium in earlier disease settings.

What was the significance of this meeting, and what does it contribute to the field?

This is the first time that this meeting has been put together, and E. David Crawford, MD, [of The University of California San Diego]; Phillip J Koo, MD, [of Banner MD Anderson Cancer Center in Phoenix, Arizona]; and Alan H, Bryce, MD, [of Mayo Clinic in Phoenix, Arizona], gathered a core group of prostate cancer experts from across the country. This group spanned urology, radiation oncology, and medical oncology, and this was a great group of experts to weigh in on some of the controversies that we’re all facing in our clinics.

[This meeting invited] discussions around active issues in prostate cancer across the landscape, from localized to metastatic disease. It was a dynamic discussion, and at times a bit of a debate with controversial [viewpoints], but overall, it’s productive to have these conversations in person, to make sure we’re on the same page.

References

1. De Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
2. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. Published online February 16, 2023. doi:10.1056/NEJMoa2214676