ASCO 2022: Updated Overall Survival Outcomes in ENZAMET (ANZUP 1304), an International, Cooperative Group Trial of Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

(UroToday.com) Since the initial presentation of the CHAARTED1 study, the standard of care for medically-eligible patients in metastatic hormone-sensitive prostate cancer (mHSPC) has been intensification of treatment with testosterone suppression to include either docetaxel chemotherapy, abiraterone hormonal therapy, or apalutamide hormonal therapy. The ENZAMET2 study (NCT02446405) expanded this treatment armamentarium to include the second generation androgen receptor inhibitor enzalutamide based on a median overall survival of 57.6 months with enzalutamide combination therapy versus 44 months for standard of care treatment (Hazard ratio for death 0.67). In this presentation, Dr. Davis first summarized his take on the prognostic variables and therapies that prolong overall survival of mHSPC.


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He then summarized the schema of the ENZAMET trial, which included patients across metastatic volume, docetaxel treatment (clinician decision), and comorbidities. Dr. Davis went on to present updated overall survival data from the prespecified analysis triggered to occur after 470 patient deaths (initial analysis was presented after 243 deaths). This corresponded to a median follow-up of 68 months. Exploratory subgroup analyses were also detailed, including whether the effect of enzalutamide was modified by metastatic timing related to time of initial prostate cancer diagnosis (de novo versus metachronous), volume status (high or low by CHAARTED definition), and whether docetaxel therapy was administered at the discretion of the treating physician.

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At a median follow-up of 68 months, the median overall survival benefit for patients treated with enzalutamide plus testosterone suppression was not reached, as compared to 73.2 months in the control group. This corresponds to a hazard ratio of death with enzalutamide of 0.70 (95% CI 0.58-0.84, p<0.001). The median 5-year survival for the enzalutamide arm was 67%.

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As overall survival is impacted by subsequent lines of therapy, Dr. Davis presented data on therapy after progression on ENZAMET. A total of 76% of patients in the control arm went on to receive a second generation anti-androgen therapy for mCRPC. A total of 39% of patients with progression on enzalutamide for mHSPC had no further treatment recorded.

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Dr. Davis then transitioned to exploratory subgroup analysis. At this juncture, and at other times in his talk, he emphasized that these were not appropriately powered to allow for reliable inferences and formal comparison, and should only be viewed as hypothesis generating.

The first exploratory analysis he presented involved OS in prespecified subgroups (but not appropriately powered for formal comparison) of early docetaxel (triplet therapy) and volume of disease at diagnosis. No statistically significant interaction p-values were determined within these subgroups. Dr. Davis asserted that there was some suggestion that patients with low-volume metastatic disease may have derived greater benefit from enzalutamide, this is confounded by the better prognosis of this disease state at baseline.

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He then showed Kaplain-Meier survival estimates for patients stratified by treatment, metastatic timing, and volume status. Though not formally powered for comparison, the red circle in the synchronous high volume patients suggests a window of opportunity where triplet therapy with testosterone suppression, docetaxel and enzalutamide may be beneficial.

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From a PSA progression-free survival perspective, Dr. Davis noted that many patients in the synchronous (de novo) and metachronous metastatic groups have yet to experience PSA progression.

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Dr. Davis ended his talk with a discussion of the strengths, limitations and conclusions of this follow-up analysis of ENZAMET. These are summarized in the slides below.

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In conclusion, the addition of enzalutamide to testosterone suppression in mHSPC confers an overall survival benefit. Interestingly, the median overall survival of patients in this study in the control arm who received docetaxel was quite long at over 60 months. One hypothesis is that these patients were taken off study early and had prompt initiation of second generation anti-androgen therapy. The greatest benefit of triplet therapy appears to be relatively early in the disease course for patients with synchronous high-volume metastatic disease.

Presented by: Ian D. Davis, PhD, MBBS, FRACP, FAChPM, Eastern Health Clinical School, Monash University, Melbourne, Australia

Written by: Alok K. Tewari, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

References:

  1. Christopher Sweeney, Yu-Hui Chen, Michael Carducci, et al. “Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.” N Engl J Med. 2015;373:737-746
  2. Ian Davis, Andrew Martin, Martin Stockler, et al. “Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.” N Engl J Med. 2019;381:121-131. 

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