Mary Ann Johnston

Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial

BACKGROUND Cancer-induced muscle wasting begins early in the course of a patients malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer. METHODS We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844. FINDINGS Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range -2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, -4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range -5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug. INTERPRETATION Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents. FUNDING GTx.

Toremifene for Breast Cancer: A Review of 20 Years of Data

Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) > 40 years ago represented a revolutionary advance in the treatment of breast cancer. As a therapeutic class, SERMs have either estrogenic or antiestrogenic activity, depending on the target tissue and the hormonal environment. In breast tissue, SERMs are antiestrogenic, making them a major treatment option for women with hormone-sensitive breast cancer. Toremifene citrate was developed > 20 years ago with the goal of achieving efficacy similar to that of tamoxifen and with an improved safety profile. Although studies to date have not confirmed a clear safety advantage or disadvantage for toremifene, clinical data support the efficacy and safety of toremifene for the treatment of breast cancer in postmenopausal patients. Toremifene also has a pharmacokinetic profile and metabolic pathway different from that of tamoxifen, which may provide a therapeutic advantage in certain patients. In addition, because of the selective estrogenic effects of SERMs in bone and on lipid levels along with a different side effect profile compared with the aromatase inhibitors (AIs), toremifene is a viable option to the AIs for some patients. Despite a number of clinical trials and over 500,000 patient years of use, many oncologists have limited familiarity with toremifene data. This article will examine the rationale for the use of toremifene in the treatment of women with breast cancer and review data from 20 years of clinical experience with this agent.

Abstract P1-13-04: Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival

Background: Historically, androgens have been utilized for the treatment of breast cancer (BC) as the androgen receptor (AR) is the most highly expressed steroid receptor in BC (75-95% of estrogen receptor positive (ER+) and 50% of ER negative). Reports of the use of androgens in metastatic BC (MBC) indicate that women progressing on tamoxifen have the ability to respond to synthetic androgens with overall response rates in the range of 20-60%; however, these steroidal androgens also exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), such as enobosarm, offers a targeted approach of AR activation without virilization or estrogenic effects. Methods: This is a phase II proof of concept study examining the efficacy and safety of once daily enobosarm 9 mg in post-menopausal women with ER+ MBC who had responded to adjuvant and/or salvage endocrine therapy. Therapy is continued until patients display evidence of disease progression. The proportion of AR+ patients with clinical benefit response (CBR) at 6 months is the primary endpoint; defined as patients with a complete response (CR), partial response (PR), or stable disease (SD) as detailed in modified RECIST 1.1. AR status of metastatic disease will be correlated with CBR. Serum prostate specific antigen (PSA) will be assessed as a biomarker of AR activation by drug. Secondary endpoint is progression free survival (PFS). Results: Patient demographics: mean age 63.7 years, mean time from diagnosis 11.0 years, 72.7% prior chemotherapy, 89% (17/19) AR+. After a median follow-up of 81 days (range 7-304 days), preliminary results of 22 patients: 9 SD as best response, median duration 212 days. Current disposition of patients: 15 PD after a median 80 days (range 15-304 days), 4 SD (1 on treatment for Conclusions: Enobosarm demonstrates promise as a novel endocrine agent for AR+ MBC. The primary endpoint has been achieved, with 6/17 AR+ patients meeting statistical threshold for success (35% CBR at 6 months). Serum PSA appears to be a surrogate marker for AR activity associated with enobosarm administration. Based upon these favorable preliminary findings, a larger phase II study is anticipated. Citation Format: Beth Overmoyer, Pedro Sanz-Altimira, Ann H Partridge, Martine Extermann, Jane Liu, Eric Winer, Nancy Lin, Michael Hassett, Leroy Parker, Ryan Taylor, Michael Hancock, Susan Small, Mary Ann Johnston. Enobosarm for the treatment of metastatic, estrogen and androgen receptor positive, breast cancer. Final results of the primary endpoint and current progression free survival [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-04.

Abstract OT2-01-07: A phase 2 open label, multi-center, multinational study investigating the efficacy and safety of GTx-024 on advanced, androgen receptor-positive triple negative breast cancer (AR+ TNBC)

Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer (BC) with expression seen in up to 95% of estrogen receptor positive (ER+) and up to 50% of ER negative disease. Historically, steroidal androgens exhibited virilizing side effects, thus limiting clinical use. In TNBC, the expression of AR and androgen synthesizing enzymes is associated with lower proliferation, lower tumor grade, better overall survival, and more favorable clinical outcomes as compared to those patients with TNBC not expressing AR. Data from two trials targeting AR in TNBC indicates low level but encouraging clinical activity. A non-steroidal, tissue-selective, AR modulator (SARM), such as GTx-024, offers a targeted approach of AR activation in AR+ TNBC without virilization or estrogenic effects. Trial Design: Open label, multicenter, multinational, Phase 2 study for the treatment of advanced or metastatic TNBC. Subjects will receive GTx-024, 18 mg orally (PO) daily, continued until evidence of disease progression or toxicity. Subjects whose tumors demonstrate Clinical Benefit (CB) will be treated on study drug until progression. Eligibility Criteria: Inclusion: Female, ≥18 years old, confirmed AR+ (≥10% staining) TNBC (confirmed by medical history), up to 1-2 prior chemotherapy regimens, available archived tumor tissue, measurable or bone-only disease, ECOG 0 or 1, with prior toxicities from chemotherapy resolved. Exclusion: Life expectancy Specific Aims: The primary aim is to measure the proportion of AR+ subjects with CB at 16 weeks; defined as subjects with a complete response (CR), partial response (PR), or stable disease (SD); per modified RECIST 1.1. Secondary endpoints include: objective response rate, progression free survival, and time to progression. Statistical Methods: Simon9s two-stage (optimal) design will be used to assess primary efficacy, requiring up to 41 evaluable subjects; i.e., subjects with centrally confirmed AR+ who receive at least one dose of study drug. The first stage will be assessed among the first 21 evaluable subjects. If at least 2/21 achieve CB per modified RECIST 1.1 at 16 weeks, then the trial will proceed to the second stage of recruitment of up to a total of 41 subjects in the evaluable subset of the Full Analysis Set. Otherwise, the trial will be discontinued for lack of efficacy. The trial will test for an unacceptably low CBR of ≤5% versus a CBR more consistent with ≥20%. Target Accrual: Up to 55 subjects will be enrolled. Trial Information: www.gtxinc.com Citation Format: Rugo H, Overmoyer B, Schwartzberg L, Palmieri C, Taylor R, Hancock M, Small S, Johnston MA. A phase 2 open label, multi-center, multinational study investigating the efficacy and safety of GTx-024 on advanced, androgen receptor-positive triple negative breast cancer (AR+ TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-07.

Abstract OT2-01-06: Phase 2 open label, multinational, randomized, parallel design study investigating the efficacy and safety of GTx-024 on metastatic (MET) or locally advanced (LA) ER+/AR+ breast cancer (BC) in postmenopausal (PM) women

Background: Historically, androgens have been utilized for the treatment of BC as the androgen receptor (AR) is the most highly expressed steroid receptor (∼95% in estrogen receptor positive (ER+), ∼50% in ER negative). However, steroidal androgens often exhibit virilizing side effects, thus limiting clinical use. A non-steroidal, tissue-selective, AR modulator (SARM), GTx-024, offers a targeted approach of AR activation in ER+/AR+ BC without virilization or estrogenic effects. A previous Phase 2 study of 9 mg GTx-024 in MET ER+ BC demonstrated proof-of-concept, with 6/17 ER+/AR+ patients (pts) exhibiting clinical benefit (CB) following 6 months (m) of treatment. Increasing the dose to 18 mg has the potential for greater efficacy without compromising safety. Trial Design: Open label, multinational, randomized, parallel design Phase 2 study to assess the efficacy and safety of GTx-024 in PM ER+/AR+ BC. Pts will be randomized to receive GTx-024, 9 mg or 18 mg orally (PO) daily. Therapy continues until disease progression. Pts achieving a CB can be treated for 12 m following the initiation of study treatment; those demonstrating continued CB are offered continuation in a safety extension study under a separate protocol. Eligibility Criteria: Inclusion: Informed consent, female, ≥18 years (yr), PM, MET or LA ER+ (≥1% staining) BC, HER2 negative, ≥1 prior hormonal treatment for BC (≥6 m response for MET; ≥3 yr response for adjuvant), provide archived tumor tissue for AR determination, measurable or bone-only disease, evidence of PD within 30 days (d), ECOG 0 or 1. Exclusion: >1 prior chemotherapy regimen for MET, uncontrolled CNS metastases, radiotherapy ≤14d prior to enrollment, major surgery ≤28d prior to enrollment, currently receiving hormone replacement, hepatitis B/C positive, HIV positive, another active cancer. Specific Aims: Primary endpoint: proportion of AR+ pts in each arm achieving a CB response (CBR) at 24 weeks (wks). CBR defined as pts with a complete response (CR), partial response (PR), or stable disease (SD); per modified RECIST 1.1. Secondary endpoints: objective response rate, progression free survival, time to progression, and duration of response. Statistical Methods: Simon9s two-stage (optimal) design will be used to assess primary efficacy, requiring up to 88 evaluable pts; i.e., pts with centrally confirmed AR+ who receive at least one dose of study drug. The trial will test for an unacceptably low CBR of ≤10% versus a CBR ≥30%. There is no intent to statistically compare the two dose arms, but to determine whether either or both doses result in an acceptable CBR. Target Accrual: Up to 118 pts will be enrolled. The first stage will be assessed in each arm among the first 18 evaluable pts. If at least 3/18 exhibit CB at 24 wks, then the arm will proceed to the second stage of recruitment up to a total of 44 pts. Otherwise, the arm will be discontinued for lack of efficacy. Trial Information: www.gtxinc.com Citation Format: Overmoyer B, Rugo H, Schwartzberg L, Palmieri C, Taylor R, Hancock M, Small S, Johnston MA. Phase 2 open label, multinational, randomized, parallel design study investigating the efficacy and safety of GTx-024 on metastatic (MET) or locally advanced (LA) ER+/AR+ breast cancer (BC) in postmenopausal (PM) women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-06.