ASCO GU 2018: A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer

San Francisco, CA ( Androgen-axis inhibitors, specifically enzalutamide and abiraterone, have revolutionized the management of advanced prostate cancer. However, despite their efficacy, all men eventually develop resistance and progress. Identification of these resistance mechanisms may enable development of therapies to resensitize PCa to these agents, thereby delaying the need for secondary treatments.

The group from UC Davis, known for their work in CRPC, identified that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors – thereby allowing persistant activation of the androgen axis despite androgen-axis inhibition. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7.

They then discovered that indomethacin (Indo), an established medication for gout, inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. Anecdotally, one patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted the design of this clinical trial. The benefit of this type of trial is that this is an established medication with known acceptable side effect profile.

Below, a summary of the protocol is detailed. To-date 4 patients have been enrolled. No dose limiting toxicities have been noted. PSA response seen in 3 of 4 patients.

This is an investigator initiated single arm phase 1b/2 trial, hence the primary focus is on safety and tolerability. Patients with metastatic CRPC who have failed abiraterone, but have adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl, are eligible.

Patients will initially receive Enza 160 mg po daily and Indo 50 mg po three times a day to determine toxicity (Phase Ib). The Phase II expansion will subsequently enroll 26 patients with 21 evaluable patients.

The planned sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone.

Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy.

This is an intriguing study with important potential to re-purpose one medication for alternative, novel uses.

Presented by: Chong-xian Pan, MD, PhD

Co-Authors: Primo Lara, Christopher P. Evans, Mamta Parikh, Ralph de Vere White, Marc Dall'era, Chengfei Liu, Daniel Robles, Allen Gao

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA