A First-in-Human Phase 1 Study of a Novel Selective Androgen Receptor Modulator (SARM), RAD140, in ER+/HER2- Metastatic Breast Cancer

Clin Breast Cancer. 2022 Jan;22(1):67-77. doi: 10.1016/j.clbc.2021.08.003. Epub 2021 Aug 20.


Introduction/background: This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM).

Patients and methods: This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement.

Results: Twenty-two (21 AR+) heavily pretreated mBC patients were enrolled. Dose levels included 50 mg (n = 6), 100 mg (n = 13), and 150 mg (n = 3) once daily (QD). Most frequent (> 10%) treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each). Grade 3/4 TEAEs occurred in 16 (72.7%) patients and included elevations in AST/ALT and hypophosphatemia (22.7% each). Treatment-related TEAEs occurred in 17 per 22 patients (77.3%); 7 (31.8%) were Grade 3; none were Grade 4. The half-life (t1/2) of 44.7 hours supported QD dosing. At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response. Overall, clinical benefit rate at 24 weeks was 18.2%, and median progression-free survival was 2.3 months. SHBG decreased in 18 per 18 patients, and PSA increased in 16 per 20 patients. Paired baseline and on-treatment tumor biopsies demonstrated AR engagement.

Conclusion: RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

Keywords: AR-targeted agent; ESR1; advanced breast cancer; dose-escalation study; estrogen-receptor positive.

Publication types

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

MeSH terms

  • Administration, Oral
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • ErbB Receptors
  • Female
  • Humans
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Metastasis
  • Nitriles / therapeutic use*
  • Oxadiazoles / therapeutic use*


  • Antineoplastic Agents
  • Nitriles
  • Oxadiazoles
  • RAD140
  • EGFR protein, human
  • ErbB Receptors