Abstract
BackgroundThe androgen receptor (AR) is expressed in ∼ 90% of ER+ BC. Androgen-based therapies have had response rates up to 20-25%, but are not in common use due to poor tissue selectivity, potential aromatization to estrogen, and emergence of ER-targeted agents. RAD140 is an oral nonsteroidal selective AR modulator (SARM) with tissue-selective AR agonist activity in BC cells but attenuated activity in other androgen-responsive tissues. RAD140 inhibited the growth of multiple in vitro and in vivo AR+/ER+ BC models. MethodsThis is a phase 1 study of RAD140 with a 3+3 design. The primary objective is safety and to determine the maximum tolerated dose (MTD); secondary objectives are pharmacokinetics and antitumor activity. Key eligibility criteria are: ER+/HER2- and inoperable/metastatic BC (mBC), post-menopausal, and ineligible for standard therapy. AR status is by immunohistochemistry (IHC). Sex hormone-binding globulin (SHBG) and serum prostate specific antigen (PSA) are used to assess AR-engagement. ResultsDose escalation (n=16 patients, pts) has been completed. Median age = 58 years, 88% visceral disease, and 94% AR+ by IHC. Median number of prior lines of therapy for mBC = 5; prior fulvestrant 88%, aromatase inhibitor (i) 100%, CDK4/6i 94%, mTORi/PI3Ki 50%, chemotherapy 94%. Dose levels were 50mg (n=6), 100mg (n=7), and 150mg (n=3) QD. Median time on treatment = 8 (range <1-25) wk. The most frequent (>30%) adverse events were elevated ALT/AST, decreased weight/appetite, and constipation. Dose-limiting toxicities (all grade 3 and reversible) were hypophosphatemia (n=2; 150mg) and elevated ALT/AST (n=2; 50 and 100mg). No drug-related deaths occurred. There was 1 partial response (PR, 100mg) and 2 pts with stable disease ≥12 wk. The time to PR was 15.9 wk and the duration was 8.6+ wk. SHBG decreased in 12/12 pts and PSA increased in 10/14 pts, most notably in the pt with PR who remains on treatment at 7mo. ConclusionsThe provisional MTD for RAD140 is 100mg QD. RAD140 is a novel oral AR-targeted agent for treatment of ER+ mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity. NCT03088527. Clinical trial identificationNCT03088527. Legal entity responsible for the studyRadius Health, Inc. FundingRadius Health, Inc. DisclosureE. Hamilton: Advisory / Consultancy: Flatiron Health; Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Clovis Oncology; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Research grant / Funding (institution), Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Sysmex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. N. Vidula: Research grant / Funding (institution): Radius Health; Research grant / Funding (institution): Daewha; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer. C. Ma: Research grant / Funding (self): Eisai; Research grant / Funding (self): Puma; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Syndex; Advisory / Consultancy: Seattle Genetics. R.G. Bagley: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. Z. Yu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M. Annett: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weitzman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M.G. Conlan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weise: Speaker Bureau / Expert testimony: Array BioPharma. All other authors have declared no conflicts of interest.
Published Version
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