The phase 1b patients received single-agent LY 200 mg twice daily (BID) for 1 week prior to starting LY plus enzalutamide. Phase 2 patients were randomized 1:1 to 160 mg daily enzalutamide with placebo or 200 mg BID LY on a 28-day cycle. The primary objective was PSA progression-free survival (PFS: serological, radiographic [rPFS], or death) by PCWG2 criteria. Secondary objectives were rPFS, safety, decline in PSA, and pharmacokinetics. Exploratory biomarker analyses included outcomes by the presence of androgen receptor variant 7 (AR-V7). Ninety-two primary PFS events were needed for the study to have at least 80% power at one-sided alpha=0.20. The schema for the study is as follows:
LY plus enzalutamide was tolerable during phase 1b with one dose-limiting toxicity observed in 13 enrolled patients. Mean LY exposures remained in an efficacious range despite a 30% average decrease when combined with enzalutamide. In phase 2, 129 patients were randomized to LY plus enzalutamide (n=65) and placebo plus enzalutamide (n=64). Patients in each group were well-balanced for demographic and clinical features, including 23% of each arm having previously received docetaxel. Median PSA-PFS was 3.7 months (LY plus enzalutamide) vs 2.9 months (placebo plus enzalutamide) (HR 0.65, 95% CI 0.43-0.99). There was no difference in rPFS (HR 0.68, 95% CI 0.40-1.13):
In the subgroup analysis by AR-V7, patients that were AR-V7 negative that received combination therapy had an improvement in rPFS (HR 0.52, 95% CI 0.28-0.95), whereas AR-V7 positive patients did not (small sample size, n=17). Patients receiving LY plus enzalutamide had more fatigue (63.1% vs 51.6%), nausea (58.5% vs 32.8%), and diarrhea (56.9% vs 15.6%) compared to patients receiving placebo plus enzalutamide.
Several conclusions can be drawn from this study:
- Combination LY plus enzalutamide had a manageable safely profile
- The primary endpoint of PSA-PFS was met, which was supported by the exploratory endpoint finding of a clinically meaningful improvement in rPFS in AR-V7 negative patients
- Biomarker data may provide important insights into future development strategies
Presented by: Christopher Sweeney, MD, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Co-Authors: Ivor John Percent, Sunil Babu, Jennifer Cultrera, Bryan Allyn Mehlhaff, Oscar B. Goodman, David Morris, Ian D. Schnadig, Costantine Albany, Neal D. Shore, Paul R Sieber, Susan Guba, Minmin Wang, Suhyun Kang, Volker Wacheck, Gregory P Donoho, Anna M. Szpurka, Sophie Callies, Boris K. Lin, Johanna C. Bendell; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Florida Cancer Specialists South/Sarah Cannon Research Institute, Port Charlotte, FL; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN; Florida Cancer Specialists/Sarah Cannon Research Institute, Leesburg, FL; Oregon Urology Institute, Springfield, OR; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Urology Associates, PC, Nashville, TN; Compass Oncology, Tualatin, OR; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Carolina Urologic Research Center, Myrtle Beach, SC; Lancaster Urology, Lancaster, PA; Eli Lilly and Company, Indianapolis, IN; Eli Lilly Gesellschaft M.B.H., Wien, Austria; Eli Lilly and Co, Indianapolis, IN; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA
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