ASCO 2019: Phase 1b/2 Study of Enzalutamide with LY3023414 or Placebo in Patients with mCRPC After Progression on Abiraterone

Chicago, IL ( The phosphoinositide 3-kinase (PI3K)/mTOR signaling pathway is frequently activated in solid and hematologic malignancies. Previously, a phase I study of the novel and potent PI3K/mTOR dual kinase inhibitor LY3023414 (LY) exhibited a favorable safety profile.1 Abiraterone and enzalutamide are approved for metastatic CRPC (mCRPC) and the activity of enzalutamide after abiraterone showed a radiographic progression-free survival (rPFS) of ~4 months in all patients and 6 months in those with ≥6 months of prior abiraterone.2 The combined inhibition of the androgen receptor and PI3K/mTOR may result in improved clinical benefit for men with mCRPC. Christopher Sweeney, MD, and colleagues presented results of a double-blind, placebo-controlled, randomized Phase 1b/2 study of LY with or without enzalutamide (a dual PI3K/mTOR inhibitor) in patients with mCRPC who progressed on abiraterone.

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
Clinical trial information: NCT02407054

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

  1. Bendell JC, Varghese AM, Hyman DM, et al. A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res. 2018;24(14):3253-3262.
  2. Suzman DL, Luber B, Schweizer MT, et al. Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. Prostate 2014;74(13):1278-1285.