QLH12016, an Oral AR-Targeting PROTAC Degrader, Shows Promise in Reshaping Treatment Paradigm for Metastatic Castration-Resistant Prostate Cancer

This study is an ongoing Phase I, open-label clinical trial aimed at evaluating the safety, tolerability, and antitumor activity of QLH12016 in heavily pretreated mCRPC patients.

Inclusion Criteria: Patients must have received at least one novel endocrine therapy and one taxane-based chemotherapy (excluding those with medical contraindications, intolerance, or refusal) and be undergoing castration therapy, regardless of the status of the androgen receptor ligand-binding domain (LBD).

Dosing Regimen: Patients will take QLH12016 orally once daily (using a BOIN dose escalation design) until disease progression, intolerable toxicity, or other discontinuation events occur. The Dose-Limiting Toxicity (DLT) observation period is 35 days after the first dose.

Primary endpoint: DLT and maximum tolerated dose (MTD)/recommended Phase II dose (RP2D).

As of the data cutoff on February 14, 2025, a total of 36 patients were enrolled and received QLH12016 treatment at doses of 100-1200mg QD. All patients had metastatic disease, with 28% having visceral metastases (lung 11.1%, liver 2.8%); 69.4% were LBD wild-type, and 30.6% had LBD mutations (including L702H mutation).

1) Safety: Significant advantages in gastrointestinal and hematological toxicity

No DLT events were observed in the study. Treatment-related adverse events (TRAEs) occurred in 91.7% of patients, with a ≥3 grade TRAE incidence rate of 38.9%. The most common TRAEs were anemia (63.9%), fatigue (47.2%), and weight loss (41.7%).

Notably, the incidence of ≥3 grade gastrointestinal-related TRAE was 0%, and hematological ≥3 grade TRAE was also very rare (anemia 5.6%, neutropenia 2.8%), this safety profile is significantly better than traditional chemotherapy or novel endocrine drugs, laying a good foundation for long-term treatment.

2) Efficacy: Breakthrough LBD state limitation, all dose groups showed activity

QLH12016 Demonstrates Encouraging Antitumor Activity in Patients Across Different LBD States:The median progression-free survival (mPFS) in the overall population was 7.4 months (95% CI: 3.7-9.4); the mPFS in the 600mg dose group (n=13) reached 9.0 months (95% CI: 1.9-NE); the mPFS in the 900mg dose group (n=10) has not yet been reached (NR, 95% CI: 1.7-NE). This data indicates that, regardless of whether patients have AR LBD mutations (including drug resistance driver mutation L702H), QLH12016 can exert efficacy and is expected to overcome the drug resistance bottleneck of traditional anti-androgen drugs.

The therapeutic advantage of QLH12016 stems from the unique mechanism of PROTAC technology: it simultaneously binds to AR and E3 ubiquitin ligase, inducing AR protein ubiquitination and subsequent proteasomal degradation, thereby completely blocking the AR signaling pathway.¹This "degradation-based inhibition" can not only overcome drug resistance caused by AR overexpression and mutations, but also reduce off-target effects and enhance safety.

From a clinical perspective, this study is the first to validate the feasibility of QLH12016 in heavily pretreated mCRPC patients: its excellent gastrointestinal and hematological safety profile supports its potential as monotherapy or combination therapy for advanced prostate cancer; efficacy that overcomes LBD status limitations offers a new treatment option for all mCRPC patients, including those with traditional anti-androgen resistance.