Overcoming AR Mutations in Prostate Cancer: Phase 1 Results of HRS-5041

A new investigational drug, HRS-5041, may offer a compelling strategy to overcome resistance to androgen receptor (AR)-targeted therapies.. Unlike traditional AR inhibitors, HRS-5041 is an oral androgen receptor degrader designed to eliminate the receptor itself, including clinically relevant mutant forms.

In a phase 1, 156 patients with mCRPC were treated with HRS-5041. All patients had previously progressed on at least one NHA, and most had also received taxane chemotherapy. Importantly, the cohort included both patients with AR-LBD mutations and those with wild-type AR, allowing for direct comparison of efficacy across biologically distinct subgroups.

AR-LBD mutations are largely therapy-induced (or, more precisely, therapy-selected), which is why they are quite common in the castration-resistant setting.

The trial explored a wide range of doses, ultimately identifying two promising regimens: 360 mg once daily and 240 mg twice daily.

The results demonstrate clear antitumor activity, particularly at higher doses. Prostate-specific antigen (PSA) declines of at least 50% were observed in up to 48.4% of patients with AR-LBD mutations receiving 240 mg twice daily. Even in this heavily pretreated population, such response rates are notable.

Radiographic progression-free survival (rPFS) outcomes were also encouraging. Median rPFS reached approximately 11 months in several groups, with 8-month progression-free rates exceeding 80% in some mutation-positive cohorts.

Notably, responses were not limited to biochemical markers. Objective tumor responses were observed, including two complete responses, one of which occurred in a patient with liver metastases, a setting typically associated with aggressive disease and poor outcomes.

One of the most important findings from this study is the differential activity based on AR mutation status.
Patients harboring AR-LBD mutations consistently demonstrated higher response rates compared to those with wild-type AR.

For example, at the 240 mg twice-daily dose: PSA ≥50% decline occurred in 48.4% of mutation-positive patients versus 20% in wild-type, and 8-month rPFS reached 85.3% in mutation-positive patients

These findings strongly support the biological rationale of HRS-5041: targeting and degrading mutant AR proteins that drive resistance to conventional therapies. HRS-5041 was generally well tolerated across dose levels. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached.

The most common treatment-related adverse events included anemia, decreased appetite, and diarrhea. Grade 3 or higher adverse events occurred in approximately 13% of patients, and no treatment-related deaths were reported.

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