From the Desk of Evan Yu: “Is Testosterone Such a Bad Thing for Prostate Cancer? Rationale for Using Supraphysiologic Testosterone to Treat Castration-Resistant Prostate Cancer.”

We have known for decades that androgen deprivation offers remarkable efficacy and palliation for men with advanced prostate cancer.  Yet, soon after Charles Huggins Nobel Prize-winning discovery, many case series started emerging, describing paradoxical benefits of testosterone supplementation for patients with prostate cancer.1,2  These clinical observations seem so counterintuitive given that androgen deprivation therapy is the hallmark of treatment for advanced prostate cancer.  Yet, there may be supportive biological rationale to this surprising observation.

It is well known that prostate cancer cells adapt to a low androgen environment by upregulation of the androgen receptor.3,4  It is possible that adaptive autoregulation of the androgen receptor may sensitize prostate cancer cells to supraphysiologic androgen-induced cell death.  This theory has been supported by multiple pre-clinical studies with prostate cancer cell lines and xenografts, as supraphysiologic androgen administration inhibits cell growth.5-7  For tumors harboring androgen receptor splice variants, such as the constitutively active ARv7, these truncated androgen receptors may confer resistance to androgen receptor targeted therapies, like abiraterone acetate or enzalutamide.8  In certain androgen receptor variant xenograft models, direct androgen receptor inhibition does not affect xenograft growth, yet exogenous testosterone induces tumor regression.9  This functional result seemed to be mediated by testosterone-induced rapid downregulation of both full-length androgen receptor and ARv7 expression.

Other pre-clinical work has found that in high androgen receptor expressing cell lines, rapid transition from a castrate to a high androgen environment can induce double-strand DNA breaks, likely mediated by the enzyme, topoisomerase IIB (TOP2B).10-12  This rapid cycling seems to lead to tangling of DNA as androgen receptor-mediated transcription proceeds.  TOP2B induces transient double-strand DNA breaks to relieve these knots, before repairing them.  Hence, it is not surprising to observe synergistic effects when DNA damaging dose of radiation is applied in conjunction with supraphysiologic testosterone, in vivo.13 

As these pre-clinical studies have generated interesting hypotheses and moved into early clinical trials, approaches to avoid prostate cancer cell adaptation to either very low or very high androgen levels have led to use of intermittent high-dose testosterone therapy, termed Bipolar Androgen Therapy (BAT).  This clinical approach conforms with pre-clinical observations that supraphysiologic 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.

An early pilot study combined BAT with etoposide to potentially synergize with TOP2B effects.12  In this early trial, 7/14 (50%) patients had a significant PSA decline from baseline.  Soft tissue tumor shrinkage was also observed.   Preliminary data from the phase II RESTORE trial, where patients progressing on enzalutamide were administered BAT (n=30), have shown 9/30 (30%) of patients to have ≥50% PSA decline from baseline.14  Additionally, clinical/radiographic progression-free survival of 8.6 months was observed.  These early trials have also shown BAT to be well tolerated, and there are anecdotes of some patients reporting increased energy, vigor and a sense of well being.  The TRANSFORMER trial is a recently accrued trial, randomizing patients with metastatic castration-resistant prostate cancer who previously progressed on abiraterone acetate to BAT vs. enzalutamide (NCT02286921).  We eagerly await results from this trial.

As one considers the sum of the clinical data in this arena, it is important to recognize that these more contemporary trials with supraphysiologic testosterone therapy in metastatic castration-resistant prostate cancer are distinct from some earlier attempts.  There have been a couple of clinical trials that have used exogenous testosterone therapy to achieve up to physiologic androgen levels.15,16  These trials saw no objective responses and only 1 patient had a ≥50% PSA decline from baseline.  It is felt that there is a major functional difference on prostate cancer between eugonadal and supraphysiologic testosterone levels in this patient population.

Although there is still limited data for the concept of supraphysiologic testosterone, there is increasing theoretical, pre-clinical and early clinical data that warrants further exploration in a well-controlled setting beyond anecdotal use.  Only with properly well-designed trials will this field advance beyond haphazard use in the clinical setting.  Fortunately, there are multiple ongoing trials (see below) that are actively accruing patients.  Many patients are eager to enroll on these trials, as some have heard anecdotes that there may not only be potential for antitumor efficacy, but there may be some “good side effects” to being on supraphysiologic testosterone!  

Ongoing Trials of Supraphysiologic Testosterone Therapy for Castration-resistant Prostate Cancer


Written by: Evan Yu, MD

References
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  10. Denmeade SR, Isaacs JT.  Prostate 2010; 70:1600-7.
  11. Haffner MC, Aryee MJ, Toubaji A, et al.  Nat Genet 2010; 42:668-75.
  12. Schweizer MT, Antonarakis ES, Wang H, et al.  Sci Transl Med 2015; 7:269ra2.
  13. Hedayati M, Haffner MC, Coulter JB, et al.  Clin Cancer Res 2016; 22:3310-9.
  14. Teply BA, Wang H, Luber B, et al.  Lancet Oncol 2018; 19:76-86.
  15. Szmulewitz R, Mohile S, Posadas E, et al.  Eur Urol 2009; 56:97-103.
  16. Morris MJ, Huang D, Kelly WK, et al.  Eur Urol 2009; 56:237-44.
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