ASCO 2017: Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC): A phase 1/2 clinical trial

Chicago, IL (UroToday.com) Abiraterone acetate, a CYP17A inhibitor, is now a well-established treatment option for metastatic castration-resistant prostate cancer (mCRPC), regardless of prior docetaxel chemotherapy treatment, based on the results of the COU-AA-301 and COU-AA-302. studies.1,2 However, abiraterone administration was approved along with the administration of prednisone 5 mg twice daily, due to the risk of mineralocorticoid excess from suppression of the glucocorticoid synthesis.

ASN001, a novel non-steroidal CYP17 lyase inhibitor, selectively inhibits the sex steroid synthesis over glucocorticoid synthesis, resulting in a theoretical lower risk of mineralocorticoid excess (ME). As such, the authors postulate that prednisone co-administration may not be necessary. In this phase 1/2 multi-center open-label trial, they first assessed dose efficacy in a dose-escalation study, followed by safety and clinical efficacy in the second phase. Though they allowed pre-treated patients in the first phase, only treatment-naïve (no prior enzalutamide or abiraterone) patients were included in the second phase.

Results:
At this time, 27 total patients have been enrolled. Based on phase 1 data, the optimal dose was determined to be less than 400 mg daily. With primarily Grade 1-2 adverse events and only four patients developing experienced asymptomatic, reversible Grade 3 ALT/AST elevation on 400 mg daily dosing (resolved with dose reduction), it appears to be well tolerated. Importantly, no patients have been placed on prednisone and there have been no episodes of mineralocorticoid excess, uncontrolled hypertension or hypokalemia.

Enrollment for the second phase has begun, with patients being treated with doses lower than 400 mg to further evaluate safety and efficacy. With treatment, testosterone decrease to below quantifiable limits and DHEA decrease of up to 80% was observed.

In terms of preliminary clinical outcomes, they have noted stable disease for up to 18+ months despite prior abi/enza exposure in patients in the first phase. In the phase 2 treatment naïve cohorts, PSA decline of > 50% for up to 37+ weeks duration was observed in 3 of 4 patients at starting doses of 300/400mg. Enrollment is completed, but study is ongoing.

ASN001 appears to be a promising CYP17A lyase inhibitor with more selective inhibition of the sex steroid synthesis pathway, without requiring co-administration of prednisone. In conjunction with good tolerability and encouraging early results, we look forward to updated clinical outcomes.

Presented By: Jorge A. Garcia, MD, Hematology and Medical Oncology, Cleveland Clinic Main Campis, Cleveland, OH

Co-Authors: Robert Dreicer, Allan J. Pantuck, Naomi B. Haas, Ulka N. Vaishampayan, Niranjan Sathyanarayana Rao, Louis J. Denis, Anthony W. Tolcher

Institution(s): Cleveland Clinic Taussig Cancer Insitute, Cleveland, OH; University of Virginia School of Medicine, Charlottesville, VA; Institute of Urologic Oncology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; Abramson Cancer Center, Philadelphia, PA; Karmanos Cancer Institute, Detroit, MI; Asana BioSciences, LLC, Lawrenceville, NJ; START, San Antonio, TX

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

References:
1. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. doi: 10.1056/NEJMoa1209096. Epub 2012 Dec 10. Erratum in: N Engl J Med. 2013 Feb 7;368(6):584.

2. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.Lancet Oncol. 2012 Oct;13(10):983-92. doi: 10.1016/S1470-2045(12)70379-0. Epub 2012 Sep 18. Erratum in: Lancet Oncol. 2012 Nov;13(11):e464. Lancet Oncol. 2014 Aug;15(9):e365.
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