Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Christopher Sweeney , Ivor John Percent , Sunil Babu , Jennifer Cultrera , Bryan Allyn Mehlhaff , Oscar B. Goodman Jr., 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
Background: Preclinical and phase 1 results suggest PI3K/mTOR pathway inhibition may enhance androgen receptor inhibition. We report the results of a double-blind, placebo-controlled, randomized Phase 1b/2 study of ENZ±LY (a dual PI3K/mTOR inhibitor) in pts with mCRPC who progressed on abiraterone. Methods: Phase 1b pts received single-agent LY 200 mg twice daily (BID) for 1 wk prior to starting LY+ENZ. Phase 2 pts were randomized 1:1 to 160 mg daily ENZ with PL or 200 mg BID LY on a 28-d cycle. The primary objective was progression-free survival (PFS: serological, radiographic [rPFS], or death) by PCWG2 criteria. Secondary objectives were rPFS, safety, decline in PSA, and PK. Exploratory biomarker analyses included outcomes by presence of androgen receptor variant 7 (AR-V7). 92 primary PFS events were needed for the study to have at least 80% power at one-sided alpha=0.20. Results: LY+ENZ was tolerable during Phase 1b with 1 dose limiting toxicity observed in 13 enrolled pts. Mean LY exposures remained in an efficacious range despite a 30% average decrease when combined with ENZ. In Phase 2, 129 pts were randomized to LY+ENZ (N=65) and PL+ENZ (N=64) (Table). Median PCWG2-PFS was 3.7 mos (LY+ENZ) vs 2.9 mos (PL+ENZ) (HR 0.66, 95% CI 0.43, 0.99; p-value 0.0208). Conclusions: Combination LY+ENZ had a clinically manageable safety profile. The primary end-point of PCWG2-PFS was met and is supported by a clinically meaningful delay in rPFS in AR-V7 negative pts. The biomarker data provide important insights to inform future development strategies. Clinical trial information: NCT02407054
LY+ENZ N=65a | PL+ENZ N=64a | Unstratified HR (95% CI), P-value | |
---|---|---|---|
rPFS, median (mos) | 7.5 | 5.3 | 0.68 (0.41, 1.14), 0.069 |
rPFS AR-V7 negative, median (mos) | 13.2 (n=51) | 5.3 (n=54) | 0.52 (0.28, 0.95), 0.028 |
rPFS AR-V7 positive, median (mos) | 5.5 (n=9) | 3.6 (n=8) | 0.99 (0.27, 3.63), 0.991 |
>50% reduction in PSA, % | 20 | 25 | |
Adverse event (AE), All / Grade ≥3, % | 98 / 48 | 98 / 42 | |
Discontinuation due to AE, % | 20 | 6 | |
Fatigue b | 29 / 23 / 11 | 28 / 20 / 3 | |
Nausea b | 23 / 28 / 8 | 20 / 11 / 2 | |
Diarrhea b | 28 / 23 / 6 | 8 / 6 / 2 |
a Number of pts, unless stated otherwise b Treatment-emergent AEs in >30% of all pts, Grade 1 / 2 / ≥3, %
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