Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study

Abstract

Summary Background Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. Methods We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0–2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. Findings Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15–49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33–71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3–4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3–4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. Interpretation BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT ...

Androgen‐responsive tripartite motif 36 enhances tumor‐suppressive effect by regulating apoptosis‐related pathway in prostate cancer

“…Androgen-repressed human PC cells were repressed by DHT in vitro in a concentration-dependent manner. 26 In addition, a phase II multicohort study by Teply et al 27 has shown that bipolar androgen therapy is clinically effective for CRPC. Therefore, it is tempting to speculate that the tumor-suppressive function of TRIM36 might be involved in the molecular mechanisms of bipolar androgen therapy.…”

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

“…The exploitation of enhanced AR stability using high‐dose testosterone is addressed in a recent clinical trial for bipolar androgen therapy (BAT) of patients with Enz‐resistant CRPC. BAT, which is composed of applying supraphysiological androgen levels within repeated cycles of androgen deprivation and supplementation at high doses, re‐sensitized metastatic CRPC patients to Enz therapy . It is suggested that the sudden switch in the androgen levels provide less time for adaptive responses of AR‐signaling …”

“…BAT, which is composed of applying supraphysiological androgen levels within repeated cycles of androgen deprivation and supplementation at high doses, re-sensitized metastatic CRPC patients to Enz therapy. 10 It is suggested that the sudden switch in the androgen levels provide less time for adaptive responses of AR-signaling. 10 In recent years, AR splice variants have come into prominence, primarily because of their ability to confer resistance to treatment.…”

“…10 It is suggested that the sudden switch in the androgen levels provide less time for adaptive responses of AR-signaling. 10 In recent years, AR splice variants have come into prominence, primarily because of their ability to confer resistance to treatment. AR variant 7 (AR-V7) has been associated clinically with CRPC and resistance to abiraterone (Abi) or Enz.…”

The what, when, and why of human prostate cancer xenografts

“…While this adaptive increase in AR facilitates their continuous growth in a castrate level of serum T (ie, <0.2 ng/mL or <0.7 nM), this paradoxically sensitizes CRPC cells to growth inhibition and death when these cancer cells are rapidly switched from a low castration level to a high (ie, >3 ng/mL or >10 nM) level of androgen. Indeed, this is the basis for clinical trials using Bipolar Androgen Therapy (ie, BAT), which cycles metastatic castration‐resistant patients rapidly between short episodic periods of pharmacologically high serum T back to castrate levels of low serum T …”