Targeted Therapies Both Refine and Raise Questions About CRPC Treatment Decision-Making

Evan Y. Yu, MD

Metastatic castration-resistant prostate cancer (mCRPC) management trends may continue to sway in favor of using PARP inhibitor–based combination therapy in the first-line setting as opposed to sequencing PARP inhibitors before or after androgen receptor pathway inhibitors (ARPIs), although additional research is needed to confirm the benefit of this approach, according to Evan Y. Yu, MD.

In an interview with OncLive® following a State of the Science Summit™ on genitourinary cancers, which he co-chaired, Yu discussed factors that influence PARP inhibitor treatment selection for patients with mCRPC, as well as what the future may hold regarding defining the optimal settings and sequencing for this class of agents in this disease.

He highlighted how data from the phase 3 TALAPRO-2 trial (NCT03395197) have set enzalutamide (Xtandi) plus talazoparib (Talzenna) as a first-line standard for mCRPC management and, together with future clinical trial findings, may support a paradigm shift toward the increased use of combination regimens in this setting. Notably, enzalutamide plus talazoparib was FDA approved in 2023 for the treatment of patients with homologous recombination repair (HRR) gene–mutated mCRPC based on findings from TALAPRO-2, in which the median radiographic progression-free survival (rPFS) was not reached with the combination vs 13.8 months with enzalutamide monotherapy (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).1 Additionally, the final overall survival (OS) findings from this trial showed an improvement with the combination (n = 402) vs enzalutamide alone (n = 403), with respective median OS lengths of 45.8 months (95% CI, 39.4-50.8) and 37.0 months (95% CI, 34.1-40.4; HR, 0.796 [95% CI, 0.661-0.958; P = .0155]).2

“I can’t declare [enzalutamide plus talazoparib] the overall winner, but I can say that it probably has stronger data [compared with the other combinations approved for patients with mCRPC],” Yu said in the interview. “[It has generated] an OS benefit in non–BRCA-mutated disease, [as well as in patients with] HRR gene [alterations], such as those in CDK12, where other PARP inhibitors have not shown clear benefit.”

Yu is the section head of Medical Oncology and a professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington. He is also the medical director of Clinical Research Support at Fred Hutchinson/University of Washington (UW)/Seattle Children’s Cancer Consortium, as well as the assistant fellowship director and a professor in the Division of Hematology and Oncology at the UW School of Medicine.

OncLive: What clinical data help you choose between the variety of PARP inhibitors that are approved for patients with CRPC?

Yu: There’s monotherapy, and there’s combination therapy. For monotherapy, we have an FDA approval for rucaparib [Rubraca] for the post-chemotherapy disease [setting for patients with BRCA1- or BRCA2-mutated mCRPC]. We also have a monotherapy FDA approval for olaparib [(Lynparza) for the treatment of patients with mCRPC with mutations in 15 HRR pathway genes; this agent] can be used pre- or post-chemotherapy.

However, the latest and greatest [development with this class of agents] has been combination therapy for first-line mCRPC. We have FDA approvals now for olaparib plus abiraterone acetate [Zytiga] and niraparib [Zejula] plus abiraterone acetate for [the treatment of patients with] BRCA1/2-mutated mCRPC in the first line. Those approvals are based on [findings from] the phase 3 PROpel [NCT03732820] and MAGNITUDE [NCT03748641] studies, respectively.

One unique study is TALAPRO-2, [which supported the] FDA approval of enzalutamide plus talazoparib for [patients with mCRPC with alterations in at least 1 of 12 HRR pathway genes]. Interestingly, that study showed an rPFS benefit [with enzalutamide plus talazoparib vs enzalutamide alone] for patients with DNA repair alterations, as well as for those without [those alterations]. More recently, at the 2025 Genitourinary Cancers Symposium, we saw OS data [from this trial], and this is the first combination study for first-line mCRPC to show an OS benefit with an ARPI plus a PARP inhibitor [vs an ARPI alone].

However, when you break down [these findings, the OS benefit in the overall population was] still mostly driven by patients with BRCA1/2 mutations. Additionally, interestingly, patients with HRR-nondeficient [disease] had a numerical difference in [outcomes vs] those with homologous recombination–deficient [HRD] disease. However, [this difference was] not statistically significant, as the [upper bound of the 95% CI for HR] crossed 1.

I don’t envision a world where [enzalutamide plus talazoparib] gets FDA approved for all-comers. Its current FDA approval for [patients harboring alterations in 12 HRR genes] will probably get a reasonable amount of utility because, unlike the other combinations, [this regimen generated an] OS benefit. Additionally, in gene-by-gene breakdowns, there are seemingly promising results [with this combination in patients with] gene mutations that some of the other PARP inhibitors may not have [elicited]. For instance, [outcomes in patients with] CDK12 mutations look good with talazoparib plus enzalutamide.

How do the differing safety profiles of each PARP inhibitor affect your treatment decision-making?

PARP inhibitors can cause myelosuppression. The most common adverse effects [AEs] they cause are gastrointestinal AEs, such as anorexia, low-grade nausea, etc. Talazoparib may [be associated with] more myelosuppressive AEs. Most importantly, [treatment decisions] depend upon patients’ comorbidities and their tolerance of [those comorbidities and AEs].

[For instance], when we’re selecting between ARPIs, we consider everything. We think about co-pays, patient desires, comorbidities, and AEs. [Those aspects] factor into the equation with PARP inhibitors as well. [Treatment decisions are] not all about efficacy, and it’s still not clear that efficacy is definitively better with any PARP inhibitor vs another.

What is your advice for colleagues regarding the use of PARP inhibitors in combination regimens vs in sequence before or after ARPIs?

I would feel more confident using [the FDA-approved combination of enzalutamide plus talazoparib] as a combination for patients with BRCA1/2 mutations, those with HRD disease, and those [who may] have aggressive disease features. One of the arguments for not using [those agents in] combination has been that [that strategy] hasn’t clearly been shown to be better than sequencing [those agents]. If I give a patient an ARPI plus a PARP inhibitor, is that better than using an ARPI followed by a PARP inhibitor or a PARP inhibitor followed by an ARPI?

There are some data to support the use of [a PARP inhibitor in combination with an ARPI in patients with mCRPC] from the phase 2 BRCAAway study [NCT03012321]. [That trial only had approximately] 20 patients per arm, but the rPFS was better with olaparib plus abiraterone acetate than either sequence [of those agents]. That points a bit more toward using [these classes of agents in] combination. [Data with] enzalutamide plus talazoparib might also point a little more toward using these agents in combination, because there was an OS benefit [with the combination in patients with] BRCA mutations or HRD disease.

[Those are data] you could apply now when you have [a patient harboring] a BRCA mutation. In the past, maybe you [would have chosen to use a] sequence of, for example, abiraterone acetate then olaparib. Maybe now you’d want to use abiraterone acetate plus olaparib or enzalutamide plus talazoparib. [Those are considerations] that could be applicable now [with agents that are] already FDA approved, and [additional] data might start pointing a bit more in the direction that combination regimens might be better than sequencing [individual agents], although that is still not 100% definitive.

References

1. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed April 15, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
2. 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