PARP Inhibitor and ARPI Combinations Are at the Forefront of Investigations in mCRPC

Monica Chatwal, MD

PARP inhibitor and androgen receptor pathway inhibitor (ARPI) combination therapies have shown promise in patients with metastatic castration-resistant prostate cancer (mCRPC) who have BRCA mutations and homologous recombination repair (HRR) gene alterations, and their role continues to be parsed out, according to Monica Chatwal, MD.

The phase 3 TALAPRO-2 trial (NCT03395197) was the first PARP inhibitor plus ARPI combination study to show a statistically significant and clinically meaningful improvement in overall survival (OS) vs standard of care ARPI in patients with unselected as well as HRR gene–altered mCRPC.1 Final results from the study presented at the 2025 Genitourinary Cancers Symposium showed that the OS benefit with talazoparib (Talzenna) plus enzalutamide (Xtandi) vs placebo plus enzalutamide was greater in the HRR-deficient (HR, 0.542; 95% CI, 0.361-0.814) than non-deficient/unknown (HR, 0.874; 95% CI, 0.711-1.076) population. The doublet is only currently FDA approved for those with HRR gene–mutated mCRPC.2,3

Additionally, those with BRCA1/2 mutations experienced a greater OS benefit with the combination vs placebo/enzalutamide (HR, 0.497; 95% CI, 0.318-0.776) than those without a BRCA1/2 mutation (HR, 0.727; 95% CI, 0.516-1.024).4

“As a whole, [these data] continue to reiterate the fact that we don’t have enough meaningful or statistically significant data to support the use of the combination in patients who have HR-proficient disease; we don’t have strong enough data to support the use of this combination over perhaps other therapies that they could benefit from more [such as] chemotherapy or radioligand therapy for those patients who would be eligible,” Chatwal said in an interview with OncLive®. “But we are consistently seeing a significant benefit in patients with HRR alterations and those with BRCA mutations. That’s undeniable. At this point even the updated data from 2025 very consistently support that.”

In the interview, Chatwal, a medical oncologist at Moffitt Cancer Center in Tampa, Florida, detailed how the role of PARP inhibitor and ARPI combinations is shifting in mCRPC and how PARP inhibitors could be moved earlier in the treatment paradigm in the future for those with BRCA mutations. She also highlighted takeaways on the targeted therapy space as shared at an OncLive State of the Science Summit™ on genitourinary cancers, which she cochaired.

OncLive: What were key takeaways from your presentation on targeted-based therapies for prostate cancer?

Chatwal: It’s nice that we now have more data regarding the use of PARP inhibitors in combination with ARPIs, particularly in patients with HRR gene mutations, and a bit more data about specific genes involved. It’s also helpful that we have updated data about the use of [the enzalutamide plus talazoparib] combination in patients without these alterations, although the data that we currently have still seem to support the use of the combination of ARPIs and PARP inhibitors in patients with BRCA mutations. We’re still seeing the greatest benefit in patients who harbor those mutations, reiterating the need to use PARP inhibitors earlier on in the care of patients with BRCA-mutant mCRPC. We still have more to tease out regarding patients who have HR-proficient disease.

Could PARP inhibitors move up earlier in disease management for patients with CRPC?

There has been research looking at this, particularly in the localized setting I believe, and currently it has not been shown to significantly improve long-term outcomes. However, in the BRCA-mutated population, there may be a role to move up PARP inhibitors, especially in combination with other therapies as we’re seeing being done with chemotherapy and ARPIs now. Therefore, I could see this [class] moving up in combination with other therapies if we see a meaningful benefit, but it’s still going to be probably limited to patients with BRCA mutations. I truly believe that is where the need lies because we know that those patients will likely not see multiple lines of therapy as their disease progresses.

What is important to know about the synergism between PARP inhibitors and ARPIs?

It’s important to know that there is a great deal of synergism in not just one direct way; there’s a lot of overlapping bidirectionality between both PARP and androgen receptors, so when you inhibit one or the other or both, you can get this intertwined mechanism of inhibition. That was the concept behind potentially using both [agents] in patients with HRR alterations or [HRR] deficiency and those with HR-proficient [disease] to perhaps try to create an HR-deficient–like state. It’s an interesting synergism that has preclinical data showing us that there’s a lot of overlap between those 2 features of the cells. But we still need to look into this a bit more.

For patients who have a BRCA mutation, when would you use a single agent vs a combination therapy?

This is going to be an evolving space. In my patients who have not yet for whatever reason received an ARPI in the metastatic hormone-sensitive state, I would consider still using the combination therapy over PARP monotherapy because there may still be some benefit to an ARPI in that circumstance. The challenge becomes if you have a patient who is consistently on an ARPI, and they then progress. The question is still yet to be answered as to whether we can then add a PARP inhibitor to what they’re taking. The studies that were done weren’t performed to look at that, so I don’t know if you can necessarily add the PARP inhibitor.

There are some data that show that sequential therapy isn’t as good as the additive effect of the PARP inhibitor and ARPI so that’s going to be a little challenging. If I had a patient who has consistently been on an ARPI such as abiraterone acetate [Zytiga], and then they progress into the mCRPC state and have a BRCA2 alteration, I would probably opt to use PARP inhibitor monotherapy in that patient. But if a patient for whatever reason didn’t get an ARPI—though that subset is going to be very small in the future—or perhaps received an ARPI for several years and then had stable disease or stable undetectable prostate-specific antigen and decided with the guidance of their provider to take a break, then that would be a situation where I would perhaps use the combination.

How do you select between available combination therapies for patients who have mutations?

A lot of that comes down to provider preference, financial limitations [as] some are going to be a little bit easier to get covered than others, and then the current indications. Niraparib [Zejula] and olaparib [(Lynparza) which were both approved in combination with abiraterone and prednisone are available] for patients with a BRCA1/2 mutation, but we have the indication for talazoparib/enzalutamide for patients with HRR-deficient mCRPC.

References

1. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA18
2. Final TALAPRO-2 results: first-line talazoparib plus enzalutamide improves survival in unselected patients with mCRPC. ASCO Daily News. February 13, 2025. Accessed March 12, 2025. https://dailynews.ascopubs.org/do/final-talapro-2-results-first-line-talazoparib-plus-enzalutamide-improves-survival
3. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed March 12, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
4. Fizazi K, Azad A, Matsubara N, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA141. doi:10.1200/JCO.2025.43.5_suppl.LBA141