A new clinical trial is set to evaluate a promising combination therapy for men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed despite prior treatments. This novel approach pairs two cutting-edge drugs, tulmimetostat (DZR123) and JSB462 (also known as luxdegalutamide or ARV-766), each targeting different but complementary cancer pathways to improve patient outcomes.

Tulmimetostat is a potent oral inhibitor of both EZH2 and EZH1 enzymes. These enzymes play a key role in epigenetic regulation, silencing tumor suppressor genes and enabling cancer cells to repair DNA damage. By blocking EZH2 and EZH1, tulmimetostat disrupts tumor growth and sensitizes cancer cells to treatment by disabling their DNA repair mechanisms.

JSB462 is an oral androgen receptor (AR) degrader from the proteolysis-targeting chimera (PROTAC) drug class. Unlike standard AR blockers, JSB462 promotes the degradation of both normal and mutated androgen receptors, the primary drivers of prostate cancer proliferation. This targeted degradation mechanism helps overcome resistance that commonly develops with hormone therapies that merely block receptor function.

Scientific rationale and preclinical data support the synergy of this combination. Tulmimetostat impairs the cancer cells’ ability to recover from DNA damage, while JSB462 eliminates the androgen receptor signaling that fuels cancer cell survival and growth. Together, they attack two essential vulnerabilities in advanced prostate cancer, offering a potentially more effective strategy than single-agent treatments.

The upcoming clinical trial, conducted globally in multiple centers, features a two-part Phase I/II design. The initial phase involves dose escalation and optimization of the combination to identify the best tolerated and most effective dose regimen. The expanded Phase II segment compares the combination’s efficacy—measured by prostate-specific antigen (PSA) responses and tumor shrinkage—against current standard-of-care treatments in patients who have not yet received chemotherapy for mCRPC.

Previous studies of both tulmimetostat and JSB462 as single agents have demonstrated encouraging safety profiles and clinical activity. Importantly, each drug has shown antitumor activity reflected by significant PSA declines and tumor responses in heavily pretreated populations.

This combination represents a novel dual-attack approach in advanced prostate cancer, simultaneously targeting epigenetic pathways and androgen receptor signaling to delay or overcome treatment resistance.

Clinical trial.