Abstract 2549
Background
The 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.
Methods
This 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.
Results
Dose 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 50 mg (n = 6), 100 mg (n = 7), and 150 mg (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; 150 mg) and elevated ALT/AST (n = 2; 50 and 100 mg). No drug-related deaths occurred. There was 1 partial response (PR, 100 mg) 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 7 mo.
Conclusions
The provisional MTD for RAD140 is 100 mg 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 identification
NCT03088527.
Editorial acknowledgement
Legal entity responsible for the study
Radius Health, Inc.
Funding
Radius Health, Inc.
Disclosure
E. 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.
Resources from the same session
3034 - Efficacy and safety of neoadjuvant chemotherapy plus trastuzumab and pertuzumab in non-metastatic HER2-positive breast cancer in real life: NEOPEARL STUDY
Presenter: Maria Agnese Fabbri
Session: Poster Display session 2
Resources:
Abstract
4772 - Real world comparison of the impact of adjuvant capecitabine in women with high-risk triple-negative breast cancer after neoadjuvant chemotherapy
Presenter: Maysa Vilbert
Session: Poster Display session 2
Resources:
Abstract
5627 - Influence of age on the indication of adjuvant chemotherapy in early breast cancer using Oncotype DX. An analysis of 240 patients treated in the Institut Catala d’Oncologia (ICO) hospitals
Presenter: Sabela Recalde
Session: Poster Display session 2
Resources:
Abstract
3917 - Impact of delayed neoadjuvant systemic chemotherapy on survival among breast cancer patients
Presenter: Mariana Chavez Mac Gregor
Session: Poster Display session 2
Resources:
Abstract
2246 - Clinical Confirmation of Higher Exposure to Niraparib in Tumor vs Plasma in Patients With Breast Cancer
Presenter: Laura Spring
Session: Poster Display session 2
Resources:
Abstract
581 - The rationale for the effectiveness of systemic treatment of breast cancer depending on the body weight index
Presenter: Mohammad Hojouj
Session: Poster Display session 2
Resources:
Abstract
5327 - Response to neoadjuvant chemotherapy in HER2 non-overexpressing breast cancer subtypes
Presenter: Silvia Mihaela Ilie
Session: Poster Display session 2
Resources:
Abstract
3613 - Pre-specified interim analysis of the SAFE trial (NCT2236806): a 4-arm randomized, double-blind, controlled study evaluating the efficacy and safety of cardiotoxicity prevention in non-metastatic breast cancer patients treated with anthracyclines with or without trastuzumab.
Presenter: Lorenzo Livi
Session: Poster Display session 2
Resources:
Abstract
3736 - Safety of hypofractionated whole breast irradiation after conservative surgery for patients aged less than 60 years: a multi-center comparative study.
Presenter: Icro Meattini
Session: Poster Display session 2
Resources:
Abstract
5085 - Usefulness of NT-ProBNP as a biomarker of cardiotoxicity in breast cancer patients treated with trastuzumab
Presenter: Isabel Blancas López-Barajas
Session: Poster Display session 2
Resources:
Abstract