ANZUP Mini ASM 2020: ANZUP Trial Update - The ENZAMET Trial

(UroToday.com) The 2020 Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) Mini Annual Scientific Meeting (ASM) featured a session on ANZUP trial updates, including an update of the critical Phase III ENZAMET trial provided by Drs. Ian Davis, Arun Azad, and Lisa Horvath.


Dr. Davis started by recapping the 2019 publication of ENZAMET.1 This trial randomly assigned 1,125 metastatic hormone-sensitive prostate cancer (mHSPC) patients from March 31, 2014, to March 24, 2017: 562 in the non-steroidal anti-androgen and 563 in the enzalutamide arm. The trial schema is as follows:

ENZAMET trial schema

The treatment groups were well balanced for all important baseline factors. In the non-steroidal anti-androgen arm, 44% of patients were planned for early docetaxel, compared to 45% in the enzalutamide arm; 53% of patients in the non-steroidal anti-androgen arm were high volume metastatic burden compared to 52% in the enzalutamide arm. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen (PSA) progression-free survival, clinical progression-free survival, and adverse events. At the time of the first interim analysis (median follow-up of 33 months), there were 143 deaths in the non-steroidal anti-androgen arm compared to 102 deaths in the enzalutamide arm. Overall survival was significantly prolonged in the enzalutamide arm compared to the non-steroidal anti-androgen arm (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.52-0.86):

ENZAMET overall survival

Furthermore, time to PSA rise, clinical progression, or death (HR 0.39, 95% CI 0.33-0.47) and time to clinical progression (HR 0.40, 95% CI 0.33-0.49) both favored enzalutamide:

ENZAMET time to clinical progression

In the prespecified subgroup analysis of docetaxel (yes vs. no), enzalutamide significantly improved time to clinical progression among men receiving docetaxel (HR 0.48, 95% CI 0.37-0.62), but did not improve OS (HR 0.90, 95% CI 0.62-1.31). In men not receiving docetaxel, enzalutamide improved clinical progression (HR 0.34, 95% CI 0.26-0.44) and OS (HR 0.53, 95% CI 0.37-0.75):

ENZAMET clinical progression free survival

Data presented by Dr. Martin Stockler at the 2019 European Society of Medical Oncology Annual Congress (ESMO 2019) showed that satisfactory health-related quality of life (HRQL) scores over time for patients receiving enzalutamide, with a general improvement in deterioration-free survival (composite endpoint of death, clinical progression, cessation of study treatment, or a 10-point worsening from baseline in physical function, cognitive function, fatigue or global health and quality of life):

HRQL scores ENZAMET

Dr. Davis notes that there is still exciting work to come from the ENZAMET group, including the following:

  • Publication of the HRQL data
  • Health resource utilization
  • Translational work – ctDNA, tissue gene expression profiling, and whole-exome sequencing, non-genomic (lipidomics, multiplexed cytokine assays, metabolic, bone turnover, sex steroids), tissue microscopy H&E/IHC and artificial intelligence, and imaging updates (PSMA-PET)
  • More clinical data – planned analysis at 470 deaths, longer-term follow-up, assessing the effect of the docetaxel triplet on overall survival
  • Additional analyses planned include overall survival by PSA < 0.2 in various subgroups, outcomes of docetaxel x enzalutamide x volume of disease, pooled analyses or meta-analyses including ARCHES, STAMPEDE, etc.

Dr. Arun then discussed what’s coming next for the ENZAMET trial from the perspective of genomic and transcriptomic analysis. According to Dr. Arun, there are several questions that may be answerable based on data available in ENZAMET:

  • Are there prognostic markers in baseline tissue + blood samples that better stratify patients with mHSPC?
  • Are there predictive markers in baseline tissue + blood samples that optimize the use of enzalutamide (and docetaxel)?
  • Are there early on-treatment blood markers correlated with treatment outcome?
  • What is driving therapeutic failure following upfront use of enzalutamide (and docetaxel)?

As follows is the sample availability of ENZAMET patients as of November 2020:

sample availability of ENZAMET patients

There are several aims for the genomic/transcriptomic analysis as put forth by Dr. Arun, including:

     Aim 1: Genomic markers in baseline tissue

     Aim 2: Transcriptomic profile in baseline tissue

     Aim 3: Detection of ctDNA in early on-treatment plasma

     Aim 4: Genomic landscape in plasma at progression

Finally, Dr. Horvath discussed immuno-metabolic biomarkers to predict response to enzalutamide in men with mHSPC. Dr. Horvath notes that plasma lipidomics in prostate cancer is an evolving field, looking at lipids that we would normally look at in hyperlipidemia and cardiovascular disease. Among patients with metastatic castration-resistant prostate cancer (mCRPC), it has previously been shown that patients with elevated ceramide levels had poorer overall survival. Additionally, among patients with mHSPC, Dr. Horvath’s group has shown that elevated ceramides and sphingolipids correlated with earlier androgen deprivation therapy (ADT) failure. The ENZAMET biomarker study design is as follows:

ENZAMET biomarker study

What will also be assessed in ENZAMET is computational analysis further evaluating the lipidome and cytokines utilizing ctDNA (somatic/germline), tissue DNA, and tissue immune infiltrates.

Presented by: Ian Davis, MBBS, PhD, FRACP, FAChPM, Professor of Medicine, Monash University, Head of the Eastern Health Clinical School, Eastern Health Monash University, Melbourne, Australia

Arun Azad, MBBS, PhD, FRACP, Associate Professor, Peter MacCallum Cancer Center, Chair of the Translational Research Committee, ANZUP Cancer Trials Group, Melbourne, Australia

Lisa Horvath, MBBS, FRACP, PhD, Director of the Department of Medical Oncology, Senior Staff Specialist, Conjoint Chair of Medical Oncology (Genitourinary Cancers), Chris O'Brien Lifehouse, Professor of Medicine, Central Clinical School University of Sydney, Darlinghurst, Australia

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 2020 Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) Mini Annual Scientific Meeting (ASM), November 29 - 30, 2020 

Reference:

1. Davis, Ian D., Andrew J. Martin, Martin R. Stockler, Stephen Begbie, Kim N. Chi, Simon Chowdhury, Xanthi Coskinas et al. "Enzalutamide with standard first-line therapy in metastatic prostate cancer." New England Journal of Medicine 381, no. 2 (2019): 121-131.

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