INTRODUCTION AND OBJECTIVES: TAK-385 is an investigational, oral, non-peptide GnRH antagonist in late phase 2 evaluation for the management of hormone sensitive prostate cancer (HSPC). Two trials are ongoing: TAK-385 120 mg daily (QD) vs degarelix for patients (pts) requiring 6-mos neoadjuvant/adjuvant to EBRT (NCT02135445) and continuous TAK-385 80 or 120 mg QD vs leuprorelin (LEU) for advanced PC (relapse post local treatment or M1; NCT02083185; reported here). METHODS: Pts aged ≥18 yrs with biopsy-confirmed PC, baseline testosterone (T) >150 ng/dL and PSA >2 ng/mL, and candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, QD or LEU 22.5 mg SC Q12 wks, for 48 wks. The primary endpoint was effective castration rate (T <50 ng/dL) at all scheduled visits from wk 5-24. Secondary endpoints included safety, PK, PSA response and quality of life (QoL). RESULTS: At the second interim analysis (May 2015), 92% of 75 pts in the 2 TAK-385 arms (median age 73 yrs) achieved sustained castration rates (wk 5-24) vs 95% of 20 pts in the LEU arm (median age 68.5 yrs). Median T levels after 3 days of TAK-385 fell to castrate levels (36.9 ng/dL) vs the expected T flare (648.1 ng/dL) with LEU. After 2 wks, median T with TAK-385 achieved castration levels of <20 ng/dL and from wk 5-24 most pts in all arms maintained median T∼10 ng/ dL. Consistent with the onset and depth of T lowering, PSA50 after 4 wks was 81% (TAK-385) and 20% (LEU). After 24 wks, median PSA reduction was 97.3% (0.1 ng/mL, TAK-385) vs 92.4% (0.2 ng/mL, LEU). Global QoL scores after 24 wks were similar across arms (mean decrease of 6.9 points [p=0.004] from baseline score of 81.4 for TAK- 385 vs 7.4 points [p=0.131] from 79.6 for LEU. Most pronounced, significant changes from baseline occurred in 2 EORTC QLQ-PR25 subscales (sexual activity and hormonal-treatment related symptoms) and were similar across arms. TAK-385 safety profile is consistent with medical castration with to date no identified significant off-target toxicity. All-grade adverse events occurred in 91% vs 95% pts (TAK-385 vs LEU); the most common were hot flush (59/60%) and fatigue (21/15%). PK analysis showed dose-proportional plasma trough levels over >6 mos consistent with phase 1 results. CONCLUSIONS: As a GnRH antagonist with rapid T and PSA response, the long term tolerability, efficacy and QoL of TAK-385 appear comparable to LEU. A phase 3 study of TAK-385, as an option to injectable GnRH therapies for PC pts, is planned.
Shore, N. D., Bailen, J. L., Pieczonka, C., Saltzstein, D. R., Sieber, P. R., MacLean, D. B., … Saad, F. (2016). PD28-01 TESTOSTERONE LOWERING, PSA RESPONSE AND QUALITY OF LIFE IN PATIENTS WITH ADVANCED HORMONE SENSITIVE PROSTATE CANCER RECEIVING TAK-385, AN ORAL GNRH ANTAGONIST: PHASE 2 INTERIM ANALYSIS. Journal of Urology, 195(4S). https://doi.org/10.1016/j.juro.2016.02.388