LBA65 - SAKK 08/14 - IMPROVE Investigation of metformin in patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide vs. enzalutamide alone. A randomized, open label, phase II trial

Background

Enzalutamide (ENZ) is a standard treatment for mCRPC patients (pts) who progress on androgen deprivation therapy (ADT). Metformin (MF) is an oral medication for diabetes mellitus (DM). MF has both indirect and direct effects on tumour growth. In a phase 2 study, MF induced PSA responses and disease stabilization in non-diabetic mCRPC pts. Some epidemiological data suggest a benefit of MF in prostate cancer pts. There is preclinical data on synergism of ENZ and MF. The purpose of this trial is to test if ENZ + MF in pts with mCRPC progressing on ADT is more effective compared to ENZ alone.

Methods

SAKK 08/14 is a prospective multicenter, 1:1 randomized, open label, phase 2 trial. Pts with mCRPC progressing on ADT and no prior or current therapy for DM were eligible. Pts received ENZ 160mg OD alone or in combination with MF 850mg BID. The primary endpoint of the trial is disease control rate (DCR) at 15 months (mos), defined as at least stable disease maintained during trial treatment for at least 15 mos. Secondary endpoints include OS, EFS, time to PSA progression (TTPSAP), adverse events and quality of life. In order to show superiority for ENZ + MF a total of 168 evaluable pts were needed to detect a 20% difference in DCR at 15 mos (type I error 10%, power 80%).

Results

169 pts were accrued from 06/2016 - 02/2021 in 15 Swiss centers. Median follow-up was 44 mos (95%CI 39.0-48.7). The primary endpoint was not met: DCR at 15 mos was 52.4% for ENZ + MF and 56.1% for ENZ, respectively (p=0.644). There was a trend towards improved median EFS for ENZ + MF vs ENZ (19.3 (12.5, 28.1) vs. 15.1 (12.1, 21.4) mos; HR 0.87 (95%CI 0.60-1.26; p = 0.471)), median TTPSAP (15.8 (11.4, 20.6) vs. 11.0 (9.4, 13.2) mos; HR 0.71 (95%CI 0.49-1.04; p = 0.074)) and median time to pain progression (41.7 (16.9, NA) vs. 20.3 (14.2, 58.4) mos, p = 0.474)). Median OS was similar in both arms (38.7 (25.9, 50.0) and 40.9 (28.3, 51.7) mos; HR 1.13 (0.74, 1.71); p = 0.575).

Conclusions

This is the first randomized study to investigate ENZ + MF in mCRPC and it was negative for the primary endpoint. However, MF may have a modest effect on PSA dynamics and symptom control. Larger studies are needed for confirmation.

Clinical trial identification

NCT02640534.

Editorial acknowledgement

Legal entity responsible for the study

Swiss Group for Clinical Cancer Research (SAKK).

Funding

Astellas.

Disclosure

C.A. Rothermundt: Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Board: Bristol-Myers Squibb, MSD Oncology, Bayer (Schweiz) AG, IPSEN; Financial Interests, Personal, Expert Testimony: Merck; Financial Interests, Institutional, Other, Travel Costs: PharmaMar; Financial Interests, Institutional, Sponsor/Funding: Astellas. R. Cathomas: Financial Interests, Institutional, Advisory Board: Bayer, Janssen, Astellas, Sanofi, Pfizer, MSD, BMS, Roche, Merck, Debiopharm; Financial Interests, Institutional, Advisory Role: Novartis. S.I. Rothschild: Financial Interests, Institutional, Advisory Role: Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Eisai, Eli Lilly, Merck Serono, MSD, Novartis, Otsuka, Pfizer, PharmaMar, Roche Pharma, Roche Diagnostics, Sanofi Aventis, Takeda; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Merck, Roche Pharma, AbbVie, BMS, Boehringer-Ingelheim, Foundation Medicine; Financial Interests, Institutional, Other, Honoraria: Amgen, AstraZeneca, BMS, MSD Oncology, Novartis, Roche Pharma, Roche Diagnostics, Takeda; Financial Interests, Institutional, Expert Testimony: AstraZeneca, BMS, Roche Pharma; Financial Interests, Institutional, Other, Travel and Accomodation: Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Roche, Takeda, Boehringer-Ingelheim; Non-Financial Interests, Personal, Leadership Role: Vice President of the Swiss Group for Clinical Cancer Research (SAKK); Non-Financial Interests, Personal, Member: Federal Drug Commission of the Federal Office of Public Health; Financial Interests, Institutional, Advisory Board: AbbVie, Astellas, Janssen; Financial Interests, Institutional, Invited Speaker: Janssen, Sanofi. S. Gillessen: Financial Interests, Personal, Advisory Board: Amgen, MSD, Orion; Financial Interests, Personal, Other, Honoraria: Radio-televisione Svizzera Italiana (RSI), German-speaking European School of Oncology (DESO); Financial Interests, Personal, Invited Speaker: ESMO, wiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, China Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU); Financial Interests, Personal, Speaker’s Bureau: Janssen Cilag; Financial Interests, Personal, Other, Travel Grant: ProteoMEdiX, AstraZeneca; Financial Interests, Institutional, Advisory Board: AAA International, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma Tolero Pharmaceutcials; Financial Interests, Institutional, Other, Honoraria: Silvio Grasso Consulting, WebMD-Medscape; Financial Interests, Institutional, Royalties: WO2009138392. All other authors have declared no conflicts of interest.