ASCO 2017: Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC)

Chicago, IL ( Novel therapies in prostate cancer are rapidly developing. Immune checkpoint inhibitors (ICI’s) are a novel class of medications that have gained a lot of interest. With efficacy established in multiple other malignancies, its role in prostate cancer is still being determined. By blocking the immune checkpoint cascade, these agents enable a patient’s own immune system to overcome cancer’s immune evasion mechanism.

With 2 main immune checkpoint pathways, CTLA-4 and PD-1/PD-L1/PD-L2, inevitably a combination of therapies that target both pathways would be consider as potential therapeutic option.

While the introduction of enzalutamide (Enza) and abiraterone (Abi) have revolutionized the management of castration-resistant prostate cancer (CRPC), the identification of androgen-receptor variants (ARVs), specifically ARV-7, have resulted in a search for novel therapies. The presence of ARV-7 has been demonstrated to be associated with Enza and Abi resistance, as these agents work on the ligand binding domain or androgen production.1 As these patients potentially have primary resistance to Enza and Abi, alternatives may be needed.

In this phase II, open-label, multi-institutional STARVE-PC study, the authors enrolled 15 mCRPC patients with ARV7+ circulative tumor cells (CTCs) (identified using a CLIA-certified assay). Patients received Nivolumab (anti-PD-1) 3 mg/kg plus Ipilimumab (anti-CTLA4) 1 mg/kg every 3 weeks x 4 doses, then maintenance Nivo 3 mg/kg every 2 weeks. Primary endpoint was 50% PSA response rate. Secondary endpoints included objective response rate (ORR), durable progression free survival (PFS), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs.

Median follow-up was 8.4 months, median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal metastases, all had bone metastases, and 60% had ≥4 prior treatments for mCRPC. Ultimately, these are heavily pretreated men, younger men with larve volume metastatic disease. Six men (40%) had pathogenic DNA repair gene mutations (BRCA2, ATM, MSH6, FANCM, FANCA, POLH), suggesting aggressive disease.

Overall, the PSA 50% response rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in patients with DNA repair deficient (DRD+) tumors compared to patients with DNA repair proficient (DRD–) tumors.

Overall, 7/15 (46%) men had Grade 3-4 adverse events (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths during the follow-up and treatment period.

While prior studies have noted severe toxicity with this combination, in this study, the authors felt the toxicity was acceptable. As these patients had limited available options, they appear to have had promising responses to therapy. Further studies may be warranted, particularly in patients with DRD+ tumors.

Presented By: Karim Boudadi. MD

Co-Authors: Daniel L. Suzman, Brandon Luber, Hao Wang, John Silberstein, Rana Sullivan, Donna Dowling, Rana Harb, Thomas Nirschl, Ryan Vance Dittamore, Michael Anthony Carducci, Mario A. Eisenberger, Michael Haffner, Alan Meeker, James R. Eshleman, Jun Luo, Charles G. Drake, Emmanuel S. Antonarakis

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

1. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.