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Testosterone Is Not the Enemy…Reconsidering Treatment Options for Metastatic Castration-Resistant Prostate Cancer

As a physician who has treated many patients with prostate cancer, I have heard the question about testosterone supplementation countless times over the years. It comes in many varieties. Most commonly the request is to help recover energy after previous androgen deprivation therapy. However, some recognize that there may be antitumor effects in some situations. I always enter such engagements with multiple disclosures that include the fact that using testosterone for antitumor therapy is not an FDA approved regimen, it is not ideal to work for many patients, especially those who do not have castration-resistant prostate cancer (CRPC), it is not for a patient symptomatic from prostate cancer, and that the testosterone level must be driven to truly supraphysiologic levels for potential efficacy.

The first thing that needs to be addressed is the potential mechanism of action of the use of supraphysiologic testosterone. This is yet uncertain but after years of clinical anecdotes, we do have some preclinical evidence to support some potential mechanisms of action.1-3 The most likely mechanism is related to androgen receptor (AR)-mediated transcription, which results in chromatin looping. In order to overcome this stress, topoisomerase IIB (TOP2B) is recruited to AR regulated genes, which induce transient double strand breaks to relieve the chromatin loops and repair them. Under normal conditions, TOP2B allows for efficient AR-mediated transcription. However, when high AR-expressing prostate cells, often seen in CRPC, are exposed to high concentrations of androgens, this transcriptional machinery becomes overwhelmed. This leads to persistent double strand breaks and illegitimate genomic rearrangements.

Another potential mechanism is specific for tumors that harbor androgen receptor splice variants, such as the constitutively active ARv7. In certain androgen receptor variant xenograft models, tumor regression occurs as a result of exogenous testosterone exposure.4 This seems to be mediated by testosterone-induced rapid downregulation of both full-length AR and ARv7 expression.

There are many other proposed mechanisms that have support. We have seen dynamic AR copy changes on Bipolar Androgen Therapy (BAT), with both AR and MYC amplifications no longer detectable after therapy.5 Other studies have also shown that responders to BAT have downregulation of c-MYC.6

Early clinical trials did not see incredible success with exogenous testosterone therapy, as they only achieved testosterone level increases up to physiologic androgen levels.7-8 These trials saw no objective responses and only 1 of 27 patients experienced a ≥50% PSA decline from baseline. However, there is a major functional difference between eugonadal and supraphysiologic testosterone treatment of patients with CRPC.

The likely ideal methodology to avoid prostate cancer cell adaptation to either very low or very high androgen levels is to administer intermittent high-dose testosterone therapy, termed BAT, as mentioned above. This takes advantage of the observation that testosterone-induced double strand DNA breaks and apoptosis are transient. Hence, rapid cycling of high-dose testosterone could result in repeated rounds of DNA damage and enhanced antitumor effects.

The TRANSFORMER trial is the highest level of evidence we’ve seen in support of this approach. Patients with asymptomatic or minimally-symptomatic metastatic CRPC who previously progressed on abiraterone acetate were randomized to BAT vs. enzalutamide.9 The primary endpoint was radiographic progression-free survival (rPFS), but a key secondary endpoint was PSA PFS after switching from BAT to enzalutamide vs. switch from enzalutamide to BAT, starting from the time point of crossover. Although there were no differences between BAT and enzalutamide in terms of rPFS or PSA decline, we saw that BAT attenuated cross resistance. A ≥50% PSA decline was seen in 72.2% of those that switched from BAT to enzalutamide and in 21.3% of those who switched from enzalutamide to BAT. More impressive is that median PFS was 28.2 months for BAT to enzalutamide, compared to 19.6 months for enzalutamide to BAT (HR 0.44, 95% CI 0.22-0.88; p=0.02). Finally, the most impressive finding is that overall survival was superior for BAT to enzalutamide compared to enzalutamide to BAT, 37.2 months vs. 29.0 months (HR 0.48, 95% CI 0.26-0.88; p=0.0109), respectively.

The results from the TRANSFORMER trial should ignite the field to demand a randomized phase 3 trial to attempt to definitively incorporate BAT for select patients in the metastatic CRPC treatment paradigm. At this time, there are multiple actively accruing clinical trials evaluating different methodologies of BAT administration, including some rational combination regimens. Given the enthusiasm for this approach within of our community of patients, we should pay close attention to these trials and refer our patients for enrollment.

Ongoing Trials of Supraphysiologic Testosterone Therapy for patients with Castration-Resistant Prostate Cancer

  • WOMBAT trial – goal of delaying metastasis-free survival for M0 CRPC (NCT06594926)
  • Phase 1 BAT for mCRPC for safety and quality of life evaluation (NCT06305598)
  • VA-BAT – cohorts for mCRPC patients with ATM, CDK12 and CHEK2 inactivating alterations (NCT05011383)
  • HiTeCH - BAT with carboplatin for mCRPC patients with homologous recombination deficiency (NCT03522064)
  • BAT-RAD – BAT in combination with radium-223 for mCRPC (NCT04704505)
  • BAT with sipuleucel-T for mCRPC (NCT06100705)
  • SPECTRA – BAT with either etoposide or carboplatin (DNA damaging chemotherapies) for mCRPC (NCT06039371)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate 2010; 70:1600-7.
  2. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010; 42:668-75.
  3. Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med 2015; 7:269ra2.
  4. Nakata D, Nakayama K, Masaki T, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Prostate 2016; 76:1536-45.
  5. Schiff JP, Lewis BE, Ledet EM, Sartor O. Prostate-specific antigen response and eradication of androgen receptor amplification with high-dose testosterone in prostate cancer. Eur Urol 2017; 71:997-8.
  6. Sena LA, Kumar R, Sanin DE, et al. Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC. J Clin Invest 2022; 132:e162396.
  7. Szmulewitz R, Mohile S, Posadas E, et al. A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-Risk Castration-Resistant Prostate Cancer. Eur Urol 2009; 56:97-103.
  8. Morris MJ, Huang D, Kelly WK, et al. Phase 1 Trial of High-Dose Exogenous Testosterone in Patients with Castration-Resistant Metastatic Prostate. Eur Urol 2009; 56:237-44.
  9. Denmeade SR, Wang H, Agarwal N, et al. 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; 39:1371-82.