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ASCO 2024

ASCO 2024: Blood-Based Markers of Differential Efficacy of Bipolar Androgen Therapy and Enzalutamide in the Randomized TRANSFORMER Trial

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31 and June 4 was host to the Rapid Oral Abstract Session: Genitourinary Cancer - Prostate, Testicular, and Penile. Dr. Samuel Denmeade discussed the Blood-based markers of differential efficacy of bipolar androgen therapy and enzalutamide in the randomized TRANSFORMER trial.


The development of castration-resistant prostate cancer (CRPC) involves multiple molecular mechanisms. Initially, cells may enter a dormant state following androgen deprivation therapy, pausing their growth temporarily. However, they eventually escape dormancy and resume proliferation, leading to disease progression. This transition is driven by various factors. For instance, overexpression of androgen receptor (AR) protein, regardless of androgen levels, plays a role. Additionally, ligand-independent AR variants and alterations like AR gene amplification and mutation contribute to sustained AR signaling. Furthermore, intratumoral androgen synthesis provides an alternative source of androgens, fueling CRPC progression. These mechanisms highlight the adaptive nature of prostate cancer cells and the challenges in targeting CRPC effectively.1,2
These mechanisms highlight the adaptive nature of prostate cancer cells and the challenges in targeting CRPC effectively
After observing these phenomena in the laboratory, the investigators hypothesized that men with CRPC may respond to rapid cycling between polar extremes of supraphysiological and castrate testosterone levels (figure below). Adaptive downregulation of AR expression may resensitize CRPC to androgen ablative therapy.1,2Adaptive downregulation of AR expression may resensitize CRPC to androgen ablative therapy
The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study (NCT02286921) was a multicenter, open-label, randomized, phase II trial comparing monthly Bipolar Androgen Therapy (BAT) with enzalutamide. BAT has been defined as rapid cycling between high and low serum testosterone. In the TRANSFORMER trial patients were randomly assigned (1:1) to receive testosterone cypionate (400 mg intramuscularly once every 28 days) or enzalutamide (160 mg by mouth daily).1 The design of the trial is outlined below:transformer trial design
This study included 94 patients in the BAT arm and 101 in the Enzalutamide arm. TRANSFORMER demonstrated that progression-free survival 2 (PFS2) for BAT→enzalutamide was significantly longer (28.2 versus 19.6 months) than for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = 0.02). Additionally, the overall response rate was 24.2% for BAT compared to 4.2% for Enzalutamide. Notably, no significant differences in overall survival (OS) were observed (p=0.801).

The presence of androgen receptor (AR) alterations in circulating tumor DNA (ctDNA) may help identify patients who might benefit from BAT. In this study, ctDNA from sequenced patients (tested somatic cohort) was analyzed. This cohort included 62 patients, selected based on circulating tumor cells (CTC) and blinded to trial data. Of these, 33 out of 62 patients (53%) had an AR alteration, which was only linked to trial data after ctDNA mutation calling. The respective mutations were:

  • ctDNA WES, AR mutation (n=7, t878a or l702h)
  • ctDNA WGS, AR amplification (n=27)

The patient characteristics of the somatic cohort are summarized in the table below, delineating each treatment group. The sole significant difference identified was in the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) distribution between the BAT arm and the ENZA arm. Specifically, 63% of patients in the BAT arm exhibited ECOG scores of 1-2, contrasting with only 28% in the ENZA arm. 

Patients with no AR alterations treated with BAT exhibit significantly shorter PFS (p=0.006) and OS (p=0.025) compared to those treated with Enzalutamide, as illustrated in the Kaplan-Meier curves below:
Patients with no AR alterations treated with BAT exhibit significantly shorter PFS (p=0.006) and OS (p=0.025) compared to those treated with Enzalutamide
However, patients with AR alterations treated with BAT trend toward prolonged PFS and OS vs. Enzalutamide, although not significant: PFS (p=0.22), OS (p=0.058), as illustrated in the Kaplan-Meier curves below:
AR alterations treated with BAT trend toward prolonged PFS and OS vs. Enzalutamide, although not significant: PFS (p=0.22), OS (p=0.058)
Dr. Denmeade concluded his presentation with the following key takeaways:

  • The presence of AR alterations in ctDNA may identify patients who may or may not benefit from BAT
  • In this study patients with no AR alterations treated with BAT exhibit significantly shorter PFS and OS compared to those treated with Enzalutamide
  • Additional clinical trials with BAT are open and actively accruing:
  • STEP-UP (sequencing BAT and Enzalutamide)
  • APEX (sequencing BAT + Difluoromethylornithine (DFMO) with Enzalutamide)
  • BATRAD (BAT + 223 Radium)
  • AcroBAT (oral testosterone)

Presented by: Samuel R. Denmeade, MD, Professor of Oncology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between May 31st and June 4th.
Related content: Predicting Response to Bipolar Androgen Therapy: A Blood-Based Biomarker Approach - Samuel Denmeade

References

  1. Denmeade SR, Wang H, Agarwal N, Smith DC, Schweizer MT, Stein MN, Assikis V, Twardowski PW, Flaig TW, Szmulewitz RZ, Holzbeierlein JM, Hauke RJ, Sonpavde G, Garcia JA, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller CJ, Carducci MA, Markowski MC, Eisenberger MA, Antonarakis ES. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021 Apr 20;39(12):1371-1382. doi: 10.1200/JCO.20.02759. Epub 2021 Feb 22. PMID: 33617303; PMCID: PMC8274807.
  2. Markowski MC, Wang H, Sullivan R, Rifkind I, Sinibaldi V, Schweizer MT, Teply BA, Ngomba N, Fu W, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Luo J, Antonarakis ES, Denmeade SR. A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts. Eur Urol. 2021 May;79(5):692-699. doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2. PMID: 32624280; PMCID: PMC7775877.