By Fineline Cube Jiangsu Hengrui Pharmaceuticals Co., Ltd (SHA: 600276, HKG: 1276) announced that the National Medical Products Administration (NMPA) has approved a multicenter, open‑label Phase II study evaluating the quadruple combination of SHR‑4394, HRS‑5041 tablets, zeprumetostat (SHR‑2554), and rezvilutamide in patients with prostate cancer. The novel regimen addresses multiple resistance mechanisms including AR‑PROTAC degradation and EZH2 inhibition.
Clinical Trial Overview
| Item | Detail |
|---|---|
| Company | Jiangsu Hengrui Pharmaceuticals (600276.SH/1276.HK) |
| Trial Design | Multicenter, open‑label Phase II |
| Regimen | SHR‑4394 + HRS‑5041 + Zeprumetostat + Rezvilutamide |
| Primary Endpoints | Safety, tolerability, efficacy |
| Population | Prostate cancer patients (stage/specific cohort TBD) |
| Regulatory Status | NMPA IND approval granted |
Component Drug Profiles
| Drug | Mechanism | Status | Key Differentiation |
|---|---|---|---|
| SHR‑4394 | Therapeutic biological (prostate cancer) | Self‑developed, Phase II | Novel biologic targeting undisclosed pathway |
| HRS‑5041 | AR‑PROTAC small molecule | Self‑developed | Degrades wild‑type & mutant AR; overcomes resistance to 2nd‑gen AR inhibitors |
| Zeprumetostat (SHR‑2554) | EZH2 inhibitor | Approved 2025 for PTCL | Repurposed for prostate cancer; oral, highly selective |
| Rezvilutamide | 2nd‑gen AR inhibitor | Approved 2022 for mHSPC | Stronger AR inhibition, no agonistic effects vs. 1st‑gen |
Strategic Rationale: Quadruple Combo Approach
Mechanism Synergy:
- AR Blockade: Rezvilutamide (direct inhibition) + HRS‑5041 (PROTAC degradation) provides dual AR pathway suppression
- Epigenetic Modulation: Zeprumetostat (EZH2 inhibitor) addresses tumor plasticity and AR‑independent resistance
- Biologic Component: SHR‑4394 adds immune‑modulating or novel target engagement (details pending)
Resistance Management: Combination targets AR‑dependent and AR‑independent mechanisms, critical for late‑line prostate cancer where 50‑60% of patients develop resistance to enzalutamide/apalutamide.
Market Opportunity: Prostate Cancer in China
Disease Burden:
- Incidence: 120,000 new cases annually (2025), growing at 8% CAGR
- Metastatic Disease: 30‑40% present with metastatic disease → ~40,000 eligible for combination therapy
- Resistance Population: 15,000‑20,000 patients progress on 2nd‑gen AR inhibitors annually
Market Size: China prostate cancer drug market valued at ¥18 billion (2025), projected ¥35 billion by 2030. Novel combo therapies represent ¥8‑10 billion opportunity.
Revenue Potential: If successful, quadruple combo could generate ¥2‑3 billion peak sales by 2030.
Competitive Landscape
| Regimen | Company | Mechanisms | Stage | Key Limitation |
|---|---|---|---|---|
| Hengrui Quadruple | Hengrui | AR PROTAC + EZH2 + ARi + Biologic | Phase II | First multi‑mechanism combo |
| Enzalutamide + Docetaxel | Astellas | AR inhibitor + chemo | Marketed | Resistance, toxicity |
| Pluvicto + ARi | Novartis | PSMA RLT + AR inhibitor | Phase III | Limited to PSMA‑positive |
| Talzenna + Xtandi | Pfizer/Astellas | PARP + AR inhibitor | Marketed | HRR‑mutated only (~20‑25%) |
Advantage: Hengrui’s combo is the first to integrate PROTAC + EZH2 inhibition, potentially overcoming broader resistance mechanisms.
Development Pathway & Financial Impact
Phase 2 Design: Likely ~100‑150 patients with mCRPC post‑2nd‑gen AR inhibitor failure, with primary endpoint of PSA50 response rate and safety.
Timeline:
- Study Initiation: Q1 2026
- Data Readout: Q4 2026 (interim), Q3 2027 (final)
- Phase III Decision: H2 2027 (if ≥40% PSA50 response)
Investment: ¥200‑300 million for Phase II; ¥1.5‑2.0 billion for full development (Phase III ± NDA).
Financial Leverage: Combination leverages approved drugs (zeprumetostat, rezvilutamide), reducing risk and development cost vs. de novo combinations.
Forward‑Looking Statements
This brief contains forward‑looking statements regarding the quadruple combination’s clinical development, efficacy, regulatory pathway, market opportunity, and competitive positioning. Actual results may differ materially due to clinical trial outcomes, safety signals, competitive dynamics, and regulatory review timelines.-Fineline Info & Tech