Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial

BMC Med. 2022 Mar 4;20(1):84. doi: 10.1186/s12916-022-02263-x.

Abstract

Background: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC.

Methods: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12.

Results: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients.

Conclusion: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study.

Trial registration: Clinical trials.gov NCT02691975; registered February 25, 2016.

Keywords: Androgen-receptor antagonist; Castration-resistant prostate cancer; Phase 1/2 study; Prostate-specific antigen response; SHR3680.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacokinetics
  • Androgen Antagonists / therapeutic use
  • Androgen Receptor Antagonists / therapeutic use
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / pathology

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Prostate-Specific Antigen

Associated data

  • ClinicalTrials.gov/NCT02691975