Date: 2015-09-26
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the 2015 European Cancer Congress in Vienna, Austria
Company: Medivation (USA - CA) Astellas (Japan)
Product: Xtandi® (enzalutamide)
Action
mechanism: Xtandi® (enzalutamide) is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to Xtandi®. Xtandi® decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
Disease: advanced, androgen receptor (AR)-positive, triple-negative breast cancer (TNBC)
Therapeutic area: Cancer - Oncology
Country: Belgium, Canada, Ireland, Italy, Spain, UK, USA
Trial
details: The Phase 2 open label, single-arm study was initiated in June 2013 and completed enrollment in July 2014. 118 patients were enrolled in 2 Stages at sites in the United States, Canada and Europe. The primary endpoint of the trial is clinical benefit rate, defined as the proportion of patients with a best response of complete response, partial response or stable disease at ? 16 weeks. All patients receive enzalutamide at a dose of 160 mg to be taken orally once daily.(NCT01889238)
Latest
news: * On September 26, 2015, Medivation announced updated data from a Phase 2 trial evaluating the investigational use of enzalutamide as a single agent for the treatment of advanced triple-negative breast cancer (TNBC). Results from an exploratory overall survival analysis of study data were presented during an oral plenary session at the 2015 European Cancer Congress in Vienna, Austria. A novel gene expression profiling assay was developed using data derived from the Phase 2 trial in patients with advanced TNBC, with a goal of developing a diagnostic test that could select patients who may respond to enzalutamide treatment. Nearly half of the enrolled patients (47%) tested positive for the novel gene expression profiling assay. An exploratory analysis of updated overall survival data demonstrated that those TNBC patients on enzalutamide whose tumors tested positive for the gene expression profile ("diagnostic positive") have to date experienced a 10.5-month longer median survival duration compared to those patients on enzalutamide whose tumor tested negative for the gene expression profile ("diagnostic negative"). The exploratory analysis demonstrated that median overall survival to date for diagnostic positive advanced TNBC patients treated with enzalutamide was 18.0 months (95% CI: 12.0-21.3) compared with 7.5 months for diagnostic negative advanced TNBC patients treated with enzalutamide (95% CI: 4.8 - 11.2). Medivation released its initial exploratory analysis of then current overall survival data at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting in June 2015. At that time, the median overall survival in patients whose TNBC was diagnostic positive was not yet reached (95% CI: 12.9 months - not yet reached) and for those with diagnostic negative TNBC the median overall survival was 7.5 months (95% CI: 4.8 - 11.2). Medivation provided full details of the trial design in its Form 10-Q filed with the Securities and Exchange Commission on August 6, 2015. The most common (reported in ? 10% of patients) adverse events reported as related to enzalutamide treatment in the intent-to-treat population were fatigue (35%), nausea (26%), decreased appetite (13%), diarrhea (10%), and hot flush (10%). * On December 12, 2014, Medivation and Astellas Pharma announced the presentation of Stage 1 and preliminary Stage 2 data from a Phase 2 study evaluating the use of enzalutamide as a single agent for the treatment of advanced androgen receptor positive (AR+), triple negative breast cancer (TNBC). Data was presented at the 37th Annual San Antonio Breast Cancer Symposium. Title: Stage 1 Results from MDV3100-11: A 2-Stage Study of Enzalutamide (ENZA), an Androgen Receptor (AR) Inhibitor, in Advanced AR+ Triple-Negative Breast Cancer (TNBC) (Abstract # P5-19-09). Patients with any amount of AR staining by immunohistochemistry could be enrolled in the study (n=42 in Stage 1, n=118 in total). The primary endpoint was clinical benefit rate, defined as the portion of Evaluable patients (? 10% AR staining in tumor cells and a post-baseline assessment) who had a complete response, partial response, or stable disease for at least 16 weeks. There was no limit to prior therapy. In Stage 1, 26 of the 42 enrolled women comprised the Evaluable population. In the 26 Evaluable women, the primary endpoint was achieved in 42% (11 of 26) including 1 partial response in a patient with measurable disease and 1 complete response in a patient with non measurable disease. Clinical benefit rate ? 24 weeks was achieved in 35% (9 of 26). The clinical benefit rate > 16 weeks in Stage 1 was sufficiently high to enable both the expansion into Stage 2 and early rejection of the null hypothesis. * On June 26, 2013, Medivation and Astellas Pharma announced enrollment of the first patient in a global Phase 2 clinical trial evaluating enzalutamide as a single agent for the treatment of advanced, androgen receptor (AR)-positive, triple-negative breast cancer (TNBC). Medivation is conducting this study under its agreement with Astellas. The Phase 2 open label, single-arm, multicenter trial plans to enroll approximately 80 patients with AR-positive, TNBC at sites in the United States, Canada and Europe. The primary endpoint of the trial is clinical benefit rate, defined as the proportion of patients with a best response of complete response, partial response or stable disease at ? 16 weeks. All patients will receive enzalutamide at a dose of 160 mg to be taken orally once daily.
While data are not yet mature (anticipated 2015), 1 additional complete response and 3 additional partial responses have been observed to date in the additional 76 patients enrolled following Stage 1, for a total of 6 complete or partial responses in both Stages as of November 10, 2014.
The most common adverse events reported in the Stage 1 intent to treat population (n=42) were fatigue (36%), nausea (33%), diarrhea (21%), decreased appetite (21%), back pain (14%), headache (14%), hot flush (12%), insomnia (12%), vomiting (12%), pain (12%) and constipation (12%). To date, the safety and tolerability profile of the additional patients enrolled in Stage 2 are consistent with profile seen in Stage 1. Patients will continue to be monitored for safety.
