Summary Background Cancer-induced muscle wasting begins early in the course of a patient's 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.

Muscle wasting in cancer is a common and often occult condition that can occur prior to overt signs of weight loss and before a clinical diagnosis of cachexia can be made. Muscle wasting in cancer is an important and independent predictor of progressive functional impairment, decreased quality of life, and increased mortality. Although several therapeutic agents are currently in development for the treatment of muscle wasting or cachexia in cancer, the majority of these agents do not directly inhibit muscle loss. Selective androgen receptor modulators (SARMs) have the potential to increase lean body mass (LBM) and hence muscle mass, without the untoward side effects seen with traditional anabolic agents. Enobosarm, a nonsteroidal SARM, is an agent in clinical development for prevention and treatment of muscle wasting in patients with cancer (POWER 1 and 2 trials). The POWER trials are two identically designed randomized, double-blind, placebo-controlled, multicenter, and multinational phase 3 trials to assess the efficacy of enobosarm for the prevention and treatment of muscle wasting in subjects initiating first-line chemotherapy for non-small-cell lung cancer (NSCLC). To assess enobosarm’s effect on both prevention and treatment of muscle wasting, no minimum weight loss is required. These pivotal trials have pioneered the methodological and regulatory fields exploring a therapeutic agent for cancer-associated muscle wasting, a process hereby described. In each POWER trial, subjects will receive placebo (n = 150) or enobosarm 3 mg (n = 150) orally once daily for 147 days. Physical function, assessed as stair climb power (SCP), and LBM, assessed by dual-energy X-ray absorptiometry (DXA), are the co-primary efficacy endpoints in both trials assessed at day 84. Based on extensive feedback from the US Food and Drug Administration (FDA), the co-primary endpoints will be analyzed as a responder analysis. To be considered a physical function responder, a subject must have ≥10 % improvement in physical function compared to baseline. To meet the definition of response on LBM, a subject must have demonstrated no loss of LBM compared with baseline. Secondary endpoints include durability of response assessed at day 147 in those responding at day 84. A combined overall survival analysis for both studies is considered a key secondary safety endpoint. The POWER trials design was established with extensive clinical input and collaboration with regulatory agencies. The efficacy endpoints are a result of this feedback and discussion of the threshold for clinical benefit in patients at risk for muscle wasting. Full results from these studies will soon be published and will further guide the development of future anabolic trials. Clinical Trial ID: NCT01355484. https://clinicaltrials.gov/ct2/show/NCT01355484, NCT01355497. https://clinicaltrials.gov/ct2/show/NCT01355497?term=g300505&rank=1.

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.

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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 < 6 months), and 3 early discontinuations (days 7, 28, 255). Five patients have died due to PD off study. Among the 17 evaluable patients, 6 reached the primary endpoint (35.3%; 95% CI=16.6% to 59.4%) with increased PSA, thereby exceeding the pre-defined statistical threshold requiring that at least 3 of 14 patients with an AR+ metastatic lesion demonstrate clinical benefit. CR or PR has not been observed. Current six month Kaplan-Meier estimate of PFS is 43.8% (95% confidence interval=19.5% to 68.1%). Enobosarm is well-tolerated with common grade 1/2 toxicities of nausea (8%), menopausal symptoms (13%), pain (25%), fatigue (10%), weight change (4%); 5 (4%) grade 3 toxicities (3 unrelated to drug, 1 bone pain, 1 fatigue), and no grade 4 or higher toxicities reported. Final results of the study will be available in the fourth quarter of 2014. 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.