ASCO 2017: A phase II trial of abiraterone acetate (AA) without prednisone in castration resistant prostate cancer (CRPC)

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 Enzalutamide, a novel androgen axis inhibitor, was introduced as a treatment for mCRPC around the same time, and has been a competitor in the same disease space.

As both are oral agents, the decision to choose one over the other is often determined by patient comorbidities, adverse event profiles, and contraindications. However, it should be noted that abiraterone acetate administration was approved along with the administration of prednisone 5 mg twice daily, based on clinical trial data. The indication for the prednisone is to prevent mineralocorticoid excess, as abiraterone suppresses the adrenal androgen and glucocorticoid pathways. The concomitant administration of prednisone with abiraterone makes enzalutamide a slightly more appealing option in an effort to reduce medication administration.

In this study, the authors question the need for prednisone administration in patients receiving abiraterone for castration-resistant prostate cancer (CRPC). This is a phase II multi-center, single-arm study to assess the proportion of men treated with abiraterone that require prednisone for mineralocorticoid excess (ME).

Patients included in the study were men with CRPC who had well controlled blood pressure (< 140/90 on ≤3 agents) and a normal ( ≥3.5 mmol/L) potassium level. They all received abiraterone 1000 mg daily monotherapy to start.

Patients who developed hypertension were treated with anti-hypertensives and/or a mineralocorticoid antagonist (MA) first, and were put on steroids if unresponsive. Similarly, hypokalemia was treated with supplementation or a MA. Patients with persistent or severe ME were initiated on prednisone. Lastly, patients who progressed on abiraterone were then put on steroids to assess clinical effect. Therapy was continued until radiographic progression, toxicity, or withdrawal.

Primary endpoint was the number of patients that required the addition of prednisone. Secondary endpoints included PSA progression, safety and toxicity, and radiographic progression.

Results:
A total of 60 patients were enrolled in this trial – generally, the group represented treatment-naïve CRPC (16 received prior chemotherapy, 6 enzalutamide, and 4 ketoconazole).

With regard to adverse events and tolerability, a significant portion had Grade 3-4 adverse events. Specifically, HTN (G3 n = 8, 13%; G4 n = 1, 2%), hypokalemia (G3 n = 4, 7%; G4 n = 0) and fatigue (G3 n = 1, 2%; G4 n = 0) predominated. Edema was not a significant adverse event in this cohort. Ultimately, 9 patients required progression to prednisone for toxicity: HTN (n = 3, 5%), hypokalemia (n = 4, 7%), and fatigue (n = 2, 3%). In summary, 14 patients had Gr3/4 toxicity and 9 required prednisone.

Of the cohort, 67% (n = 40) experienced a ≥50% PSA decline and 35% (n = 21) experienced a ≥90% decline. As a result of PSA progression, 19 patients (32%) were initiated on prednisone. Of these 19 patients, 5 patients had a PSA decline and 1 achieved a ≥50% decline. Of the 53 patients with metastatic disease, 11 (20.1%) achieved an objective response.

Limitations / Discussion Points:
- In this well-selected population, there was still a relatively high level of Grade 3-4 toxicity and proportion of patients requiring prednisone. In a general population, this number is likely to be much higher
- Only about 1/3 of the patients who were initiated on prednisone had some PSA response

While the authors view this as evidence that abiraterone can be safely administered as monotherapy, I feel the results are not that clear. In the patients treated with multiple anti-hypertensives and MA’s prior to prednisone, they could have potentially avoided polypharmacy by initiated prednisone up front. Based on the AE profile, it would likely be safer to continue concomitant administration of prednisone with abiraterone at this time. A multi-arm randomized study comparing two matched groups (one with prednisone and one without) would help clarify the situation.

Presented By: Rana R. McKay, MD, Dana-Farber Cancer Institute, Boston, MA

Co-Authors: Lillian Werner, Alexandra Jones, Atish Dipankar Choudhury, Mark Pomerantz, Christopher Sweeney, Glenn J. Bubley, Susan F. Slovin, Michael J. Morris, Philip W. Kantoff, Mary-Ellen Taplin

Institution(s): Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Cambridge, MA; Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Memorial Sloan-Kettering Cancer Center and Weil Cornell Medical College, New York, NY

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
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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