What question did this study set out to answer?

To evaluate the safety and efficacy of HRS-5041 in patients with NHA-resistant metastatic castration-resistant prostate cancer.

May 29, 2026

HRS-5041, an androgen receptor degrader, in metastatic castration-resistant prostate cancer: A phase 1, multicenter, first-in-human study.

Key Points

To evaluate the safety and efficacy of HRS-5041 in patients with NHA-resistant metastatic castration-resistant prostate cancer.
Phase 1 clinical trial enrolling patients with mCRPC who previously failed NHA and taxane chemotherapy.
Patients received HRS-5041 at varying doses including 180 mg QD and 240 mg BID during dose escalation.
Primary endpoints included dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D).
No dose-limiting toxicities were observed; MTD was not reached, with 85.3% reporting treatment-related adverse events.
In the 240 mg BID group, 48.4% of patients exhibited a PSA reduction ≥50%, showing superior efficacy compared to the 360 mg QD group.
Two patients achieved complete responses, including one with liver metastases.

Abstract

3112 Background: ADT plus NHA have been approved for PC of different stages. However, patients (pts) inevitably develop drug resistance, and AR mutations are a common cause of this resistance. HRS-5041 is a novel, oral, highly effective AR degrader that specifically targets the AR wild type (AR WT) and clinically relevant AR LBD mutants. We conducted a phase 1 trial to assess HRS-5041 in NHA-resistant mCRPC. Methods: Pts with mCRPC who had progressed on ≥1 NHA and ≥1 taxane chemo (unless refused or not indicated to chemo) were eligible. Pts orally received HRS-5041 at 30–540 mg QD or 240–300 mg BID during dose-escalation (DE), followed by dose or indication expansion at 180–360 mg QD or 240-300 mg BID. 240 mg BID and 360 mg QD were selected for dose optimization. The primary endpoints were DLT, MTD, and RP2D. Results: As of Dec. 12, 2025, 156 pts were enrolled, including 77 with AR-LBD mutation and 79 with AR-LBD WT. During DE, no DLT occurred. MTD was not reached. TRAEs were reported in 133 (85.3%) pts; the most common were anemia (38.5%), decreased appetite (25.6%), and diarrhea (24.4%). Grade ≥3 TRAEs and serious TRAEs occurred in 20 (12.8%) and 4 (2.6%) pts. No TRAEs led to death. Among all evaluable pts, rate of PSA reduction ≥50% was 0 for 1 pt at 30 mg QD, 0 for 4 pts at 90 mg QD, 17.4% for 23 pts at 180 mg QD, 32.1% for 53 pts at 360 mg QD, 40.0% for 5 pts at 540 mg QD, 35.7% for 56 pts at 240 mg BID, and 11.1% for 9 pts at 300 mg BID. Data by AR-LBD status for expanded doses are shown in table. Both 360mg QD and 240mg BID groups showed excellent PSA response rates and rPFSs, regardless of AR-LBD status. Among pts with AR-LBD mutations, the 240 mg BID group showed a superior rate of PSA reduction ≥50% and a higher 8-month rPFS rate than the 360 mg QD group. Notably, 2 patients in the 240 mg BID group achieved CR, including 1 with liver metastases. Conclusions: HRS-5041 showed tolerable safety and promising antitumor activity in pretreated mCRPC. A phase 3 study is currently underway in mCRPC pts with AR-LBD mutation, with a recommended dose of 240mg BID. Clinical trial information: NCT05942001 . Efficacy outcomes. Dose 180 mg QD 180 mg QD 360 mg QD 360 mg QD 240 mg BID 240 mg BID AR-LBD status AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT PSA reduction ≥30% * 5 (50.0) 1 (7.7) 15 (48.4) 8 (36.4) 17 (54.8) 7 (28.0) PSA reduction ≥50% * 3 (30.0) 1 (7.7) 10 (32.3) 7 (31.8) 15 (48.4) 5 (20.0) rPFS, mo † NR (2.2–NR) 5.8 (2.1–8.6) 11.0 (5.5–NR) 13.8 (8.2–NR) 11.0 (8.2–NR) NR (3.5–NR) 8-month rPFS rate † 53.3 (17.7–79.6) 32.6 (5.8–64.3) 58.1 (35.6–75.2) 82.9 (55.7–94.2) 85.3 (60.2–95.1) 71.2 (46.4–86.0) ORR # 2 (66.7) 0 0 0 3 (42.9) 1 (11.1) Data are n (%) or median (95% CI). * Assessed in pts who had at least one post-baseline PSA assessment or who discontinued treatment due to death/clinical progression w

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