Phase 2 Trial For a New Triplet Therapy: SHR3680 (Rezvilutamide), HS-20093 and SHR2554

This Phase II study investigates the efficacy and safety of three investigational agents: SHR3680 (rezvilutamide), HS-20093, and SHR2554, aiming to enhance outcomes in metastatic prostate cancer through dual-pathway inhibition.

SHR3680, a selective androgen receptor (AR) antagonist, represents the latest generation of hormonal therapy designed to inhibit the AR signaling axis, a critical driver of prostate cancer growth and progression. Its clinical validation has demonstrated significant improvements in radiographic progression-free survival and overall survival, surpassing earlier agents (enzalutamide) with a favorable safety profile featuring minimal central nervous system effects. These attributes lay the foundation for its role as a backbone therapy in the current trial.

HS-20093 is a novel antibody-drug conjugate targeting the B7-H3 surface protein, which exhibits consistently high expression across prostate cancer types and stages. This ADC harnesses the specificity of an anti-B7-H3 antibody to deliver a potent cytotoxic payload selectively to tumor cells, sparing normal tissues. The choice of B7-H3 as a target is not incidental: androgen deprivation therapy indirectly enhances B7-H3 expression, making tumor cells more vulnerable to this targeted approach. Early-phase studies in various solid tumors have revealed promising response rates and manageable toxicities, inspiring combination with AR-directed therapies to overcome resistance and tumor heterogeneity.

Complementing these modalities is SHR2554, an oral inhibitor of Enhancer of Zeste Homolog 2 (EZH2), a key epigenetic regulator implicated in prostate cancer progression and treatment resistance. EZH2 controls gene silencing via histone methylation, orchestrating tumor-promoting programs and modulating androgen receptor activity. Its inhibition can reverse epigenetic suppression, restore sensitivity to hormonal therapies, and impede aggressive tumor phenotypes, including neuroendocrine differentiation. SHR2554 has shown encouraging efficacy in hematologic malignancies and epithelioid sarcoma, with an acceptable safety profile, supporting further exploration in prostate cancer.

The scientific rationale for combining these agents centers on their complementary mechanisms. HS-20093 exploits the upregulated B7-H3 antigen induced by AR blockade, creating a therapeutic vulnerability enhanced by co-administration with SHR3680. SHR2554 disrupts epigenetic mechanisms that contribute to resistance, working synergistically with AR inhibition to suppress tumor growth and potentially enhance anti-tumor immunity.

Primary endpoints reflect these mechanistic hypotheses: the trial assesses durable prostate-specific antigen (PSA) responses, including the rate of undetectable PSA at six months and sustained PSA reductions at two years—biomarkers strongly correlated with improved clinical outcomes in metastatic settings. Early clinical data from related studies underscore the potential for these agents to produce meaningful tumor control with favorable tolerability.

Clinical trial.