An open-label phase 2 trial was performed to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to induce a >= 50% decrease in prostate-specific antigen (PSA) decline by day 90, modulate free testosterone and sex hormone -binding globulin (SHBG) levels, and affect estrogen deficiency -related adverse events in men with castratation-resistant prostate cancer. The 250 mg/d cohort met statistical significance for the PSA decline rate. SHBG levels were increased, there were beneficial effects on hot flashes, and there was a minimal rate of venous thromboembolic events. Introduction: Novel estrogen therapy has the potential to be efficacious, with a favorable adverse event profile, in castration-resistant prostate cancer (CRPC). We performed a phase 2 trial to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to result in a >= 50% PSA decline by day 90, modulate free testosterone and sex hormone-binding globulin (SHBG) levels, and affect estrogen deficiency adverse events. Patients and Methods: CRPC patients received GTx-758 in two dose cohorts, 125 and 250 mg/d. The primary endpoint was the proportion of subjects who experienced a >= 50% PSA decline by day 90. Secondary endpoints included changes in testosterone, SHBG, bone turnover markers, and hot flashes, as well as safety. Results: Four (10.5%) of 38 (95% CI, 2.9, 24.8; P = .120) and 10 (25.6%) of 39 patients (95% CI, 13.0, 42.1; P .001) in the GTx-758 125 and 250 mg/d cohorts, respectively, experienced >= 50% PSA decline. SHBG was increased, providing a mechanism for notable decreases in free testosterone. In the 250 mg/d cohort, 9 men presented with moderate to severe hot flashes, and after 12 weeks, 4 (44%) of 9 reported either mild or no hot flashes (P = .001). The rate of venous thromboembolic events was 0% and 5.1% in the 125 and 250 mg/d arms, respectively. Conclusion: GTx-758 has clinical activity for CRPC in a dose-dependent fashion. GTx-758 resulted in a reduction in hot flashes. On the basis of these findings, further clinical investigation of novel estrogen therapies is warranted. (C) 2020 Elsevier Inc. All rights reserved.

Abstract 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.

Purpose: Muscle wasting in cancer patients leads to decline in physical function. >50% of lung cancer patients have muscle wasting at diagnosis, increasing to >80% prior to death. Data shows cancer patients with muscle wasting are less likely to tolerate chemotherapy, have worse outcomes, have decreased quality of life (QoL), and exhibit shorter survival. Literature shows that a 10% improvement in physical function is a substantial clinically meaningful benefit. We conducted a randomized, double-blind, placebo controlled study to assess the effect of enobosarm on muscle wasting and physical function in cancer patients. The purpose of this analysis is to examine the relationship between QoL and physical function response based on patient age.

Purpose: Cachexia has been defined as >5% weight loss; however, limited data exists on the prevention and treatment of muscle wasting prior to becoming cachectic. Cancer-induced muscle wasting begins early in the disease process, resulting in decreased physical function and other detrimental consequences. Cancer patients with muscle wasting are less able to tolerate chemotherapy, have worse treatment outcomes, lose independence, and exhibit shorter overall survival. We conducted a randomized, double-blind, placebo controlled study to assess the effect of enobosarm on muscle wasting and physical function in cancer patients. The purpose of this analysis is to examine the physical function response in subjects by age and extent of weight loss at baseline.