Investigational and Established Biomarkers Guide Ongoing CRPC Therapy Developments

Evan Y. Yu, MD

Novel enzalutamide (Xtandi)–based combination regimens are gaining momentum for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and may reshape the management of this disease for patients with distinct molecular profiles, 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 emphasized the potential role of enzalutamide in combination with the EZH2 inhibitor mevrometostat (PF-06821497) for the treatment of patients with abiraterone-pretreated mCRPC. In a phase 1 dose-expansion trial (NCT03460977), the combination (n = 41) generated a median radiographic progression-free survival (rPFS) of 14.3 months (95% CI, 7.5-not evaluable) vs 6.2 months (95% CI, 4.1-13.9) with enzalutamide alone (n = 40; HR, 0.51; 95% CI, 0.28-0.95).1

He also explained where enzalutamide plus radium-223 might fit into the mCRPC treatment paradigm pending regulatory approval. The phase 3 PEACE-3 trial (NCT02194842) showed that the combination (n = 222) elicited a median rPFS of 19.4 months (95% CI, 17.1-25.3) vs 16.4 months (95% CI, 13.8-19.2) with enzalutamide alone (n = 224) in patients with bone metastatic CRPC (HR, 0.69; 95% CI, 0.54-0.87; log-rank P = .0009).2

Yu discussed further insights on the potential benefits of using PARP inhibitors in combination with androgen receptor pathway inhibitors (ARPIs) vs administering these classes of agents sequentially in another article.

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 research potentiates EZH2 as an actionable target in CRPC?

Yu: Mevrometostat is an EZH2 inhibitor that has a role in CRPC [management]. [This agent also] has a role in lineage plasticity and the development of neuroendocrine disease. It’s been known to be a driver of cell proliferation for a long time.

The original Nature paper [reporting this mechanism of action was published in] the early 2000s, and many of us thought there was going to be therapeutics [based on this mechanism] in prostate cancer. Subsequently, EZH2 inhibitors have [been developed] and gotten FDA approved for certain follicular lymphomas and sarcomas, but we haven’t seen success yet in prostate cancer. Mevrometostat is the first [of these] agents that’s given us promise [in prostate cancer]. There have been approximately 4 or 5 other attempts [to develop this class of agents] in prostate cancer.

A randomized phase [1] study [enrolled] patients with mCRPC who had previously progressed on abiraterone, who were randomly assigned to receive enzalutamide with or without mevrometostat. [Investigators] saw significant benefits in rPFS, prostate-specific antigen decline, and RECIST 1.1 soft tissue response [with enzalutamide plus mevrometostat]. There are now 2 randomized phase 3 trials in the pre-chemotherapy [mCRPC] setting: [the MEVPRO-2 trial (NCT06629779)] with enzalutamide with or without mevrometostat, and the [MEVPRO-1 trial (NCT06551324)] with mevrometostat plus enzalutamide vs [enzalutamide monotherapy or] docetaxel chemotherapy. [The findings with mevrometostat in CRPC so far have been] exciting and show a lot of promise.

How might you choose between enzalutamide-based combination regimens for patients with CRPC as the metastatic setting grows more robust?

[Many treatment advances] that are closest to being able to translate [to clinical practice are with agents] that are still not FDA approved. The PEACE-3 trial data were impressive, showing an overall survival benefit with enzalutamide and radium-223 [vs enzalutamide alone] for first-line mCRPC. [That combination is] not FDA approved yet, but it could become an option in the future for using radium earlier—in an asymptomatic disease state in combination with enzalutamide—rather than using it in a late, symptomatic disease state where it’s less apt to work well. [This strategy] could come into stark competition with the prostate-specific membrane antigen [PSMA] radioligand therapies. There’s also enzalutamide plus talazoparib [Talzenna] for first-line mCRPC. Additionally, lutetium Lu 177 vipivotide tetraxetan [(Pluvicto; formerly 177Lu-PSMA-617) is indicated for use in patients with PSMA-positive mCRPC] after [receipt of prior therapy, such as an] ARPI.

[These regimens] could all compete [with each other], because many patients are receiving ARPIs for metastatic hormone-sensitive prostate cancer. The future is going to be complex. First, we have to see regulatory approval for all these [combinations].

Based on recent and projected successes in the evolution of targeted therapies for patients with CRPC, what might be the importance of using biomarkers to drive treatment decision-making going forward?

[We may encounter] a situation where in patients with high PSMA PET uptake, we might lean [toward using PSMA radioligand therapies, whereas] in those with lower PSMA uptake, we might lean more toward [a treatment like] like enzalutamide plus radium-223. However, that’s still in the future, because we don’t have regulatory approvals for either of those [regimens] yet.

We may be [heading toward] a more biomarker-driven future where, if a patient has a BRCA1/2 mutation or homologous recombination–deficient disease on their biomarker sequencing results, we might lean more toward a regimen like enzalutamide plus talazoparib. If a patient does not have [homologous recombination repair gene mutations or high PSMA PET uptake], if enzalutamide plus radium-223 receives FDA approval, that regimen might be useful, especially if the patient has bone metastases and does not have visceral disease. The future [of mCRPC management] may be broken down based on multiple biomarkers, but it’s hard to predict. It depends upon what the regulators say, etc.

References

1. Schweizer MT, Calvo M, Moreno V, et al. Mevrometostat (PF-06821497), an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): a randomized dose-expansion study. J Clin Oncol. 2025;43(suppl 5):LBA138. doi:10.1200/JCO.2025.43.5_suppl.LBA138
2. Gillessen S, Choudhury A, Saad F, et al. LBA1 A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): first results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35(suppl 2):S1254. doi:10.1016/j.annonc.2024.08.2307