3 Things You Should Know About Advancing mCRPC Care: Targeted Sequencing, Epigenetics, and Emerging Strategies

The authors

Emerging agents targeting novel oncogenic pathways are increasingly available options for patients with metastatic castration-resistant prostate cancer (mCRPC). Here are 3 things you should know about advancing mCRPC care.

1 Treatment sequencing and personalization remain central to mCRPC management.

Standard-of-care systemic therapies for mCRPC include androgen receptor pathway inhibitors (ARPIs), chemotherapy, radiopharmaceuticals, and PARP inhibitors (Figure 1).¹ A phase 2 crossover trial (NCT02125357) showed that treatment sequence matters: abiraterone followed by enzalutamide was more effective than the reverse.² In this trial of 202 patients, group A (abiraterone ➔ enzalutamide) had a longer time to second prostate-specific antigen (PSA) progression (median 19.3 vs 15.2 months; HR, 0.66; P = .036) vs group B (enzalutamide ➔ abiraterone) and more frequent declines in PSA (≥ 30% on second-line therapy, 36% vs 4%; P < .0001). Grade 3/4 adverse events (AEs) included hypertension (27% vs 18%, respectively) and fatigue (10% vs 4%, respectively).

As with other cancers, precision medicine based on prior therapies, such as exposure to treatments for hormone-sensitive PC, tumor molecular profiles, symptoms, and comorbidities, is a goal in mCRPC. In 150 patients with mCRPC, aberrations in ETS genes, AR, TP53, and PTEN were found in 40% to 60% of cases.³ Genetic alterations in DNA repair pathways, including BRCA1/2 and ATM, occurred in 19.3% of cases. Pathogenic germline aberrations were found in 8% to 10% of patients. In total, 89% of these tumors harbored an actionable alteration that could inform individualized treatment plans.

FIGURE 1. Treatment Options for Metastatic Castration-Resistant Prostate Cancer¹

2 EZH2 plays a prominent role in lineage plasticity and is a promising epigenetic target in neuroendocrine prostate
cancer (NEPC).

EZH2 has emerged as an actionable target in mCRPC, particularly in the progression to androgen-independent NEPC.⁴ In prostate cancer, EZH2 is often overexpressed.⁵ As part of the PRC2 complex, EZH2 silences developmental genes via methylation, promoting lineage plasticity (Figure 2).⁶ Additionally, EZH2 can independently interact with AR transcriptional machinery to drive cell cycle gene expression, contributing to androgen resistance.⁷

In murine models, EZH2 modulation also enhanced responses to anti–CTLA-4 therapy.⁸ Synergy has been noted between EZH2 and PARP or AKT inhibition.^9,10 Although EZH2 inhibitors are FDA-approved for epithelioid sarcoma and follicular lymphoma, clinical results in mCRPC have been inconclusive.^11,12

FIGURE 2. EZH2-Mediated Gene Silencing Contributes to Lineage Plasticity⁶

3 Novel therapies are expanding options beyond ARPIs and PARP inhibitors.

Emerging therapies in early-phase trials in patients with mCRPC include agents with novel mechanisms of action and nonoverlapping targets that may generate synergy in combination with established treatments (Figure 3).^13-33 Proteolysis targeting chimeras (PROTACs) bring together E3 ligase and AR to ubiquitinate the latter for degradation by the cell’s proteosome.^13-15 Bispecific T-cell engagers (BiTEs) facilitate the interaction between cytotoxic T cells and prostate cancer cells expressing PSMA, STEAP1, or DLL3.^16-21 CAR T cells are engineered to express receptors for PSMA or PSCA to improve targeting of prostate cancer cells.^22-24 Antibody-drug conjugates (ADCs) bind to antigens on the surface of the prostate cancer cell and release a cytotoxic payload once internalized into the tumor cell.^25-32 Radiolabeled antibodies deliver radiotherapy directly to cancer cells expressing the appropriate ligand.³³

FIGURE 3. Emerging Mechanisms of Action in Prostate Cancer Therapies

Mevrometostat is an EZH2-targeting agent that was evaluated in combination with enzalutamide vs enzalutamide monotherapy in patients with mCRPC who have received prior abiraterone and at least 1 line of prior chemotherapy in a phase 1 study (NCT03460977).³⁴ In the randomized, dose-expansion portion of the study, the median radiographic progression-free survival (rPFS) was 14.3 months (95% CI, 7.5 months to not estimable) in patients receiving mevrometostat with enzalutamide vs 6.2 months (95% CI, 4.1-13.9) in patients receiving enzalutamide alone (HR, 0.51; 90% CI, 0.28-0.95). Treatment-related adverse events (TRAEs) of grade 3 or greater and serious TRAEs of any grade occurred in 48.8% and 36.6% of patients in the combination arm vs 22.5% and 2.5% of patients in the monotherapy arm, respectively. Phase 3 trials are underway to evaluate mevrometostat in combination with enzalutamide in patients with mCRPC who have been previously treated with abiraterone (MEVPRO-1; NCT06551324) or who have not been exposed to an ARPI (MEVPRO-2; NCT06629779).^35,36

Adding ARPIs to PARP inhibitors has also demonstrated a PFS benefit in patients with mCRPC. In the phase 3 PROpel trial (NCT03732820), imaging-based PFS was 24.8 months with abiraterone plus olaparib vs 16.6 months with abiraterone plus placebo (HR, 0.66; 95% CI, 0.54-0.81; P < .001).³⁷ In the phase 3 MAGNITUDE trial (NCT03748641) in patients with mCRPC harboring homologous recombination repair gene alterations, abiraterone plus prednisone with niraparib yielded an rPFS of 19.5 months vs 10.9 months without niraparib (HR, 0.55; 95% CI, 0.39-0.78; P = .0007).³⁸ And in the phase 3 TALAPRO-2 trial (NCT03395197), the median rPFS was not reached (95% CI, 27.5 months to not reached) in the enzalutamide with talazoparib arm vs 21.9 months (95% CI, 16.6-25.1) in the enzalutamide with placebo arm (HR, 0.63; 95% CI, 0.51-0.78; P < .0001).³⁹

Key References

2. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739. doi:10.1016/s1470-2045(19)30688-6

6. Parreno V, Loubiere V, Schuettengruber B, et al. Transient loss of Polycomb components induces an epigenetic cancer fate. Nature. 2024;629(8012):688-696. doi:10.1038/s41586-024-07328-w

34. 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

For full references list, visit https://www.gotoper.com/nygu25ezh2-postref