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ASCO 2019 Annual Meeting

ASCO 2019: Phase 1b/2 Study of Enzalutamide with LY3023414 or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer after Progression on Abiraterone - Medical Oncologist Perspective

Chicago, IL (UroToday.com) The PI3/AKT/mTOR pathway is one of the most commonly dysregulated pathways in cancer biology. LY3023414 (LY) is an oral PI3K/mTOR inhibitor, which has been demonstrated in vitro and in vivo dose-dependent dephosphorylation of PI3/AKT/mTOR downstream targets and may augment the anti-tumor activity of many standard of care therapies.1  In the phase I first in human study of LY, LY was well tolerated and the main dose-limiting toxicities were thrombocytopenia, hypotension, and hyperkalemia.2 There was one partial response in a patient with endometrial cancer harboring PIK3 and PTEN mutation and 47% of patients had stable disease as their best response. Another phase I study in patients with breast cancer found a partial response for a patient harboring an activating PIK3CA mutation (H1047R).3


The PI3/AKT/mTOR pathway is frequently implicated in advanced prostate cancer, and PTEN loss occurs in up to 50% of all patients. Unfortunately, prior trials targeting the mTOR pathway have been largely unsuccessful, both in the single agent and combination setting.4 One theory is that you may need to block not only the mTOR pathway but also the PI3K pathway in combination with blocking AR signaling. In a PTEN deficient mouse model, a combination of enzalutamide plus a dual PI3K/mTOR1/2 inhibitor led to tumor regression by nearly 84%. Christopher Sweeney, MBBS et al describe the outcomes here of enzalutamide with LY or placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone.

This abstract provides phase 1b data on 13 patients who have received LY+enzalutamide and 129 patients who were randomized in the phase II setting to LY+enzalutamide vs placebo+enzalutamide. All patients had mCRPC which had already progressed on abiraterone. The primary objective was progression-free survival (PFS) defined by PCWG2 criteria. For all patients, there was no significant difference between the LY group and placebo group with respect to progression-free survival (7.5 months vs 5.3 months, HR 0.68, p=0.069). However, for patients who were AR-V7 negative, the median radiographic progression-free survival (rPFS) was 13.2 months for the LY group and 5.3 for the placebo group (HR 0.52, p=0.028). For the AR-V7 positive group, there was no difference in rPFS. 20% of patients discontinued therapy in the LY group compared to 6% in the placebo group. The most common toxicities for the LY group was fatigue, nausea, and diarrhea.
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LY3023414, a dual PI3K/mTOR inhibitor, may prolong radiographic progression-free survival when added to enzalutamide compared with placebo, for patients who have progressed after abiraterone and have AR-V7 negative mCRPC. However, for patients with AR-V7 positive mCRPC, there did not appear to be any benefit. There currently are no FDA approved biomarker-directed therapies in prostate cancer although many therapeutics are being investigated in this manner (Lutetium 177 PSMA for PSMA+ patients, PARP inhibitors for patients with DNA repair defects) and LY may represent another class of therapeutics which are beneficial for patients with AR-V7 negativity.

Presented by: Christopher Sweeney, MBBS, Medical Oncologist, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Smith MC, Mader MM, Cook JA, et al. Characterization of LY3023414, a novel PI3K/mTOR dual inhibitor eliciting transient target modulation to impede tumor growth. Molecular cancer therapeutics 2016;15:2344-56.
  2. Moore KN, Varghese AM, Hyman DM, et al. A phase I, first-in-human dose study of the dual PI3K/mTOR inhibitor LY3023414 (LY) in patients (pts) with advanced cancer. American Society of Clinical Oncology; 2015.
  3. Varghese AM, Moore KN, Hamilton EP, et al. Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment-refractory advanced breast cancer patients. American Society of Clinical Oncology; 2017.
  4. Statz CM, Patterson SE, Mockus SM. mTOR inhibitors in castration-resistant prostate cancer: a systematic review. Targeted oncology 2017;12:47-59.