Purpose
Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC).
Methods
The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL).
Results
The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT.
Conclusion
This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.
Bipolar androgen therapy offers same efficacy as enzalutamide in mCRPC progressing after abiraterone, and potentially improves quality of life
Although highly effective initially, therapeutic resistance to androgen deprivation therapy inevitably occurs. Second-generation hormone therapies have become a standard therapy option, providing overall survival benefits by further inhibiting androgen receptors (AR). But resistance increases with the number of treatment lines at castration-resistant stage.
Preclinical studies have suggested that AR upregulation might induce cellular vulnerability allowing prostate cancer cells to be killed by exposure to supraphysiologic testosterone. This could lead to a downregulation of AR levels and a potential resensitisation to androgen-ablative therapies. In this phase 2 study, the authors hypothesised that such a bipolar androgen therapy (BAT) would have superior efficacy in CRPC as a result of chronic exposure to low androgen and adaptively sensitise these cells to antiandrogens.
The TRANSFORMER (multicenter, open-label, randomised) trial compared the effects of BAT versus enzalutamide in asymptomatic men with CRPC progressing on abiraterone. Patients were randomly assigned to receive testosterone cypionate (dose of 400 mg intramuscularly once every 28 days) or enzalutamide until progression or severe toxicity. Patients were concurrently maintained on continuous testosterone suppression. The primary end point was clinical or radiographic progression-free survival (PFS). 195 men were randomly assigned to receive either BAT or enzalutamide. Median follow-up time among patients was 31.9 months.
The median PFS was 5.6 months in the BAT arm versus 5.7 months in the enzalutamide arm (HR, 1.13; 95% CI, 0.82 to 1.57). Overall survival (OS) was not different between arms (32.9 v 29.0 months). Survival outcomes in men with short prior response to abiraterone (<6 months) favored BAT (HR, 0.55). Overall, 39.3% of patients initially on BAT crossed over to receive enzalutamide, whereas 47.6% of patients crossed from enzalutamide to BAT. Crossover to enzalutamide following BAT was associated with greater benefits for all secondary end points including median OS (37.1 versus 30.2). Patients who received the treatment sequence of BAT then enzalutamide had significantly longer PFS2 compared with the opposite sequence (28.2 v 19.6 months; HR, 0.44; 95% CI, 0.22 to 0.88). AR-V7 status was not predictive of clinical outcomes irrespective of the treatment received. The incidence of adverse effects was comparable in the two groups, except for fatigue (48.5% of grade1-2 on enzalutamide versus 31.5% on BAT).
The TRANSFORMER trial is interesting as it compares two diametrically opposite treatment options at 2nd line mCRPC stage, one further inhibiting the androgen-axis, the other based on overstimulation. In the present trial, BAT was not superior to enzalutamide but outcomes showed similar efficacy in terms of PFS, OS, PSA progression. Of note, enzalutamide after abiraterone has previously been found to have limited efficacy. Interestingly, BAT could improve quality of life by limiting treatment effects on fatigue and sexual function, in this specific context of patients progressing after abiraterone. Further evaluation is warranted to assess the benefit from the sequence BAT then enzalutamide in mCRPC patients previously treated by abiraterone and thereby, having a high risk of crossed resistance to a second-line new-generation hormone therapy as a single therapy.
Watch also the interview with Dr. Markowski on “Molecular and clinical characterization of metastatic castration-resistant prostate cancer (mCRPC) patients achieving deep PSA responses to bipolar androgen therapy (BAT)”.