Nadir testosterone (T) following in-situ polymer delivered, subcutaneously administered leuprolide acetate in men with prostate cancer (PCa).

Abstract

204 Background: Achieving and maintaining T suppression to castration level is the cornerstone of androgen deprivation therapy (ADT) for advanced PCa. Modern assay methodology found median T level after surgical castration to be 15ng/dL; the 2016 European Association of Urology guidelines define castration as T < 20ng/dL. Additionally, reaching nadir T < 20ng/dL is correlated with improved duration of response to ADT, time to progression or disease-specific survival (Klotz 2015), and prognosis for overall survival (Kamada 2015). To examine the effectiveness of in-situ polymer-delivered, subcutaneously-administered leuprolide acetate (SC-LA) on T suppression, nadir T was evaluated in 4 pivotal trials. Methods: Eugonadal patients with advanced PCa were treated with either 7.5 (6 doses), 22.5, 30, or 45mg (2 doses each) SC-LA lasting 1, 3, 4, or 6 months, respectively in 4 open-label, fixed-dose, pivotal trials. Serum T levels were evaluated byradioimmunoassay. T was measured 2-4 times on day 0 and once on days 1, 3, 7, and every week until the next dose, and repeated until end of study. The 45mg group had an additional measurement on day 2. LA was measured on days 0, 4, 7, 14, 21, 28, 35, 42, 49, and 56 post-injection. Nadir T was the lowest value obtained in the entire trial. Results: Across the SC-LA formulations, median LA levels were consistently between 0.1-1ng/mL from week 2 until the end of study. When pooled, 90-96% of patients achieved T≤20ng/dL by week 6 and 90-97% maintained T≤20ng/dL from weeks 6-24. Pooled analysis (n = 437) showed 99%, 97%, 91%, and 80% of patients reached nadir T≤20ng/dL, ≤10ng/dL, ≤5ng/dL, and ≤3ng/dL respectively with a median nadir T≤3 ng/dL. When comparing across all doses, > 88% of patients reached nadir T≤5ng/dL. Conclusions: Across all doses, SC-LA achieves consistent and prolonged serum LA drug delivery above 0.1ng/mL and provides favorable T suppression < 20ng/dL, which may be attributed to the in-situ forming polymeric delivery system. Multiple T measurements throughout the study confirmed that 91% of PCa patients achieved low nadir T≤5ng/dL, which may have implications for extending progression-free survival and duration of response to ADT.