ASCO 2017: A phase IV, randomized, double-blind, placebo-controlled study of continued enzalutamide post prostate-specific antigen progression in men with chemotherapy-naive mCRPC

Chicago, IL ( Enzalutamide (ENZA), an androgen receptor inhibitor, has been established as an effective treatment option for chemotherapy-naïve metastatic prostate cancer (PREVAIL trial)1. However, at the time of failure on ENZA are typically switched off the medication onto alternative agents, such as abiraterone acetate (CYP17 inhibitor). However, it is unclear if there would be an oncologic benefit to maintaining ENZA therapy, similar to continued ADT.

The PLATO study is a global randomized, double-blind, placebo-controlled, two-period study meant to evaluate the efficacy/safety of continued enzalutamide [ENZA] treatment (plus abiraterone acetate and prednisone [AA+P]) at the time of confirmed PSA progression, as opposed to switching to AA+P alone. 509 patients with chemotherapy-naïve metastatic CRPC (bone metastases on bone scan or CT scan, asymptomatic or minimally symptomatic) were enrolled, all of whom received open label ENZA during period 1 of the study, until PSA progression was noted (>2 ng/dL above nadir or 25% rise) without evidence of significant symptoms (pain). At that time, eligible patients were then randomized to one of the two treatments and assessed for the PFS, defined by either: 1) radiographic progression, 2) unequivocal clinical progression, or 3) death during the study. There was a prespecified sensitivity analysis of radiographic PFS (rPFS), and in addition, protected secondary end points were time to PSA progression (TTPP) and PSA response ≥ 50%.

Of the 509 patients enrolled, 251 were ultimately randomized to the P2 treatment arms (ENZA + abi/P, n = 126; PBO + abi/P, n = 125). 174 patients had discontinued ENZA prior to that point, and 84 patients had not shown evidence of progression. ECOG status was primarily 0 (~60%) in each cohort, and median PSA was between 11 and 14.

Median treatment duration in the second period was 5.6 months for both arms. In terms of breakdown of progression, PFS by radiographic/clinical/death was 38%/25%/2% for ENZA + abi/P and 55%/18%/1% for PBO + abi/P, respectively.

Median PFS was not significantly different: 5.7 mo for ENZA + abi/P and 5.6 mo for PBO + abi/P (hazard ratio [HR]: 0.83; p = 0.22). Interestingly, patients treated with ENZA were more likely to progress clinically (25.4% vs. 17.6%) rather than radiographically (38.1% vs. 55.2%). Median TTPP was not significantly different: 2.8 mo for both arms (HR: 0.87; p = 0.45). PSA response rate was also not statistically significant: 0.8% for ENZA + abi/P and 2.5% for PBO + abi/P, p = 0.31. Median rPFS, however, was 10.0 mo for ENZA + abi/P and 7.0 mo for PBO + abi/P (HR: 0.67; p = 0.02).

As this was a phase IV study, adverse events were assessed. The most common (≥ 15%) adverse events for ENZA + abi/P vs PBO + abi/P were back pain (21% vs 23%), hypertension (20% vs 7%), nausea (17% vs 9%), and fatigue (14% vs 15%).

Based on this, the authors conclude that while it increased certain adverse events (hypertension and nausea), maintaining ENZA did not improve PFS, TTPP or PSA response. While the rPFS was slightly improved, it does not appear to translate to improved overall PFS – the clinical relevance is uncertain.

The improved rPFS in ENZA may be due to the higher clinical progression rate in that group.

Discussion Points:
As health care costs continue to play an important focus in the discussion of management of metastatic prostate cancer, it would appear that maintaining a relatively expensive drug while not gaining significant benefit from it (and indeed, slightly higher adverse events) would not be warranted. Additionally, as both ENZA and AA both work on the same androgen axis, sequencing AA after ENZA may not have been the ideal assessment – prior studies have demonstrated common resistance mechanisms to both medications.2

Ultimately, until we know more about the appropriate sequencing of medications, maintaining ENZA while starting AA does not appear to be of any oncologic benefit.

Presented By: Gerhardt Attard

Co-Authors: Michael Borre, Howard Gurney, Yohann Loriot, Corina Andresen, Ranjith Kalleda, Trinh Pham, Mary-Ellen Taplin

Institution(s): The Institute of Cancer Research and The Royal Marsden Hospital, Sutton, United Kingdom; Aarhus University Hospital, Aarhus, Denmark; Macquarie University Hospital, Sydney, Australia; Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; Medivation, Inc., San Francisco, CA; Dana-Farber Cancer Institute, Boston, MA

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

1. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.
2. 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.

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