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ASCO 2018

ASCO 2018: Combination of Niclosamide to Target Androgen Receptor Variant 7 and Abiraterone to Target Androgen

Chicago, IL (UroToday.com) Abiraterone and enzalutamide improve survival for patients with metastatic castration resistant prostate cancer1,2. Unfortunately, 20-40% of patients have primary resistance abiraterone or enzalutamide, and essentially all patients develop secondary resistance3. Various mechanisms have been postulated for why patients develop cross resistance – one of which being the presence of androgen receptor splice variants. In particular, androgen-receptor splice variant 7 messenger RNA (AR-V7) has been well defined by as a variant which is associated with resistance to enzalutamide and abiraterone. Antonarakis and colleagues demonstrated prospectively that in a cohort of patients receiving enzalutamide, 53% of AR-V7 negative patients had a response compared to 0% of AR-V7 positive patients3.  

In this small phase I study, Dr. Pan and colleagues utilized niclosamide in combination with abiraterone in patients with progressive castration resistant prostate cancer. Niclosamide, a salicylamide derivative, was originally an anti-helminthic drug but more recently has been explored in variety of malignancies including HCC, colon cancer, and ovarian cancer4-7. In ovarian cancer cell lines, niclosamide may impact the Wnt/beta-catenin, mTOR, and STAT3 pathways. 

6 patients were treated with niclosamide/PDMX1001 at a dose of 1600 mg TID without any dose limiting toxicities. This is the dose that will be used as the phase II dose. At this dose, the trough was at least three times the target level of niclosamide.  Of the 6 patients, two have had undetectable PSAs for 16 cycles with ongoing activity and two patients have a partial response with more than 50% PSA decline. One limitation to this study is the lack of a control arm – patients were compared against historical controls. A second limitation to this study is that abiraterone is highly active in this patients and it difficult to say if these patients would have had the same response without niclosamide.  

The next step will be to test if niclosamide will be effective in the population of patients who have disease refractory to enzalutamide or abiraterone. Per Dr. Pan, the phase II study began enrolling patients last week and they will plan to enroll only patients who have progressed on enzalutamide. 

Presented By: Chong-xian Pan, MD, PhD. University of California Davis Comprehensive Cancer Center 

Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealdJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA 

References: 
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.de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England journal of medicine 2011;364:1995-2005. 
3.Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. New England Journal of Medicine 2014;371:1028-38. 
4.Burock S, Daum S, Keilholz U, Neumann K, Walther W, Stein U. Phase II trial to investigate the safety and efficacy of orally applied niclosamide in patients with metachronous or sychronous metastases of a colorectal cancer progressing after therapy: the NIKOLO trial. BMC Cancer 2018;18:297. 
5.Ming‐Hsien C, Yung‐Chuan H, Shun‐Fa Y, et al. Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist‐mediated CD10 expression. Environmental Toxicology 2018;33:659-69. 
6.Pearson RD, Hewlett EL. Niclosamide therapy for tapeworm infections. Annals of internal medicine 1985;102:550-1. 
7.Arend RC, Londoño-Joshi AI, Gangrade A, et al. Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer. Oncotarget 2016;7:86803-15.