ASCO 2019: Results from a Phase Ib/II Study of Enzalutamide and Metformin in Men with Castration Resistant Prostate Cancer

Chicago, IL ( Enzalutamide improves overall survival (OS) for patients with mCRPC, both before and after chemotherapy.1,2 However, all patients eventually progress on enzalutamide, due to androgen receptor (AR) and non-AR pathways of resistance. In preclinical models with mice bearing CWR22Rv1 xenografts, metformin was capable of reversing enzalutamide resistance and restoring sensitivity to enzalutamide.3  The mechanism of alleviating resistance is hypothesized to be the ability of metformin to activate STAT3 and inhibit TGF-β1. Cell line work has also shown that metformin was capable of inhibiting the invasion and migration of both LNCaP and C4-2 cells.3 The authors here provide the results from a phase Ib/II study of enzalutamide and metformin in men with castration-resistant prostate cancer (CRPC).
This abstract provides data on 24 patients without diabetes who were treated with metformin and enzalutamide for mCRPC. Baseline characteristics are below.
Patients were allowed to have up to 2 prior treatments for CRPC. 33% (8/24) of patients had prior docetaxel chemotherapy and 12.5% of patients had prior abiraterone (3/24). One patient had grade 3 adverse effects (AEs) including diarrhea, fatigue, hypertension, lower GI bleed, and myalgia, and one patient experienced grade 4 hallucination. One patient experienced a seizure. A PSA50 was observed in 79% of patients. In AFFIRM (Enzalutamide after chemotherapy), the PSA50 rate was 54% and in PREVAIL (enzalutamide before chemotherapy), the PSA50 rate was 78%. 
There is great interest in the potential anti-neoplastic effect of metformin for many tumor types including colon cancer, pancreatic cancer, and breast cancer. During this ASCO, Marc P. Martin, MD presented data on TAXOMET, a French prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC which did not show any benefit to adding metformin to docetaxel chemotherapy. In this small single-arm study, the addition of metformin to enzalutamide maintained the PSA50 rate which was seen in PREVAIL – however, this was not without toxicity. One patient had grade 4 hallucinations and one patient had a seizure who did not have a seizure history prior to therapy.  While seizures are a known side effect of enzalutamide, they are extremely uncommon in those patients without seizure histories – only 1 patient out of the 872 patients in PREVAIL had a seizure. The seizure, along with the hallucination, suggests that further study is necessary into the safety of this combination. 

Presented by: Mamta Parikh, MD, MS, UC Davis Comprehensive Cancer Center, Sacremento, CA 

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

  1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. The New England journal of medicine 2014;371:424-33.
  2. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 2012;367:1187-97.
  3. Liu Q, Tong D, Liu G, et al. Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT. Cell death & disease 2017;8:e3007.