The TulmiSTAR-02 study will evaluate tulmimetostat, a novel inhibitor targeting the Enhancer of Zeste Homolog 2 (EZH2) pathway, in combination with standard-of-care treatments for men with newly diagnosed or recurrent metastatic disease.

Current treatment approaches using androgen receptor pathway inhibitors like darolutamide and abiraterone have improved outcomes, but resistance mechanisms continue to limit long-term effectiveness. The addition of tulmimetostat represents an innovative approach targeting epigenetic regulation through the Polycomb Repressive Complex 2 (PRC2) system, which plays a crucial role in gene silencing and cancer progression.

Tulmimetostat, also known as DZR123, functions as a selective inhibitor of EZH2, the catalytic component of PRC2.
By modulating epigenetic modifications, tulmimetostat may overcome resistance mechanisms that allow cancer cells to survive despite androgen deprivation.

The study design encompasses both dose-finding and efficacy evaluation phases across an estimated seven-year timeline. The initial Phase I component will determine optimal dosing for tulmimetostat when combined with either darolutamide or abiraterone.

Following dose optimization, the Phase II portion will randomize 203 men with metastatic hormone-sensitive prostate cancer to receive either tulmimetostat plus darolutamide or darolutamide alone. This design enables direct comparison of the combination therapy against current standard treatment, providing clear evidence of any additional benefit. The primary endpoint focuses on biochemical response, specifically the proportion of patients achieving prostate-specific antigen levels below 0.2 ng/mL at six months, a marker associated with improved long-term outcomes.

Patient eligibility criteria reflect current clinical practice, including men with newly diagnosed metastatic disease or those experiencing recurrence after initial treatment. Participants must maintain castrate testosterone levels and have documented metastatic lesions in bone, soft tissue, or visceral organs. The trial permits certain prior therapies, including limited exposure to taxane chemotherapy and androgen receptor pathway inhibitors, recognizing the complex treatment histories many patients present with in real-world practice.

The study sponsor has committed to sharing individual participant data from the trial through qualified external researcher access, supporting broader scientific understanding of epigenetic therapies in prostate cancer.

By simultaneously blocking both pathways from the onset of metastatic disease treatment, researchers hypothesize they may prevent or delay the emergence of resistance mechanisms that ultimately limit current therapies.

The study begins enrollment in late 2025, marking another step forward in the ongoing effort to transform metastatic prostate cancer from a uniformly fatal diagnosis to a manageable chronic condition. The trial locations are still unknown, but they are expected to be in the USA and Europe, given that both the FDA and EMA have approved the study.

Clinical trial.