PSA provocation by bipolar androgen therapy may predict duration of response to first-line androgen deprivation: Updated results from the BATMAN study

Abstract

Background: Previously, we reported results from the Phase II BATMAN study (Bipolar Androgen Therapy for Men with Androgen-ablation Naïve prostate cancer). This study (NCT01750398) was designed to evaluate the safety and efficacy of a treatment regimen consisting of a 6-month lead in-phase of androgen deprivation therapy (ADT) followed by alternating 3-month intervals of bipolar androgen therapy (BAT) and ADT alone. Here we report > 5-year follow-up related to the duration of subsequent ADT, response to first-line androgen receptor inhibitors, safety, and survival in men with castration-sensitive prostate cancer treated on the BATMAN study.

Methods: Univariate Cox regression was utilized to compare overall survival between Responders who achieved a prostate-specific antigen (PSA) level of <4 ng/ml and Non-Responders who achieved a PSA level of ≥4 ng/ml after BAT/ADT. Kaplan-Meier method and Cox regression were used to assess progression-free (PFS) and overall survival (OS) on BAT and on subsequent abiraterone or enzalutamide and on the association between PSA peak during BAT and each time to event outcome.

Results: Over median follow-up of 95 months, the median PFS on ADT for the entire cohort was 47.8. Median OS has not been reached (NR). Median OS for Non-Responders is 43 months versus NR (not reached) for responders (hazard ratio [HR]: 0.176, p = 0.002). Post-BAT, the PSA50 and PSA90 responses to abiraterone or enzalutamide were 94.4% and 66.7%, respectively and median PFS was 20.6 months. Patients with peak PSA level of ≥9 ng/ml after BAT had median PFS of 20.6 months versus NR for those having PSA < 9 ng/ml (HR: 0.122, p < 0.001). Median OS was 79.6 months for patients with PSA peak of ≥9 ng/ml versus NR for those having PSA peak of <9 ng/ml (HR: 0.409, p = 0.131).

Conclusion: The use of BAT as part of first-line hormonal therapy strategy does not induce adversely affect long-term survival or induce any significant long-term adverse sequelae in patients with prostate cancer. Cycling BAT may extend the duration of ADT response and enhance response to subsequent androgen ablative therapies. The magnitude of BAT-provoked increase in PSA may predict duration of ADT response and warrants further study.

Keywords: PSA; androgen deprivation; bipolar androgen therapy; castration-sensitive.

FIGURE 1

Schematic showing treatment schedule of original Bipolar Androgen Therapy for Men with Androgen-ablation Naïve prostate cancer (BATMAN) study

FIGURE 2

Kaplan–Meier curves for overall survival (A) of entire cohort; (B) of Responders (PSA < 4 ng/ml on resuming androgen deprivation therapy (ADT) at end of study (blue line) versus Non-Responders (PSA≥ 4 ng/ml) (red line).

FIGURE 3

(A) Waterfall plot of best PSA response to treatment with Abiraterone or Enzalutamide at time of progression on androgen deprivation; (B) Kaplan–Meier curve for PSA progression-free survival on abiraterone or enzalutamide; (C) Swimmer’s plot showing duration of castration sensitivity (blue), interval before starting second-line therapy (orange) and duration of time on abiraterone or enzalutamide (gray).

FIGURE 4

(A) Change in PSA levels over course of therapy in Responders and Non-Responders. PSA peak after three cycles of BAT indicated by black arrows. Blue-dotted line indicates PSA level of 9 ng/ml. Kaplan–Meier curves for (B) PSA progression-free survival and (C) overall survival of patients with PSA peak after 3 cycles of BAT of <9 ng/ml (blue line) versus PSA ≥ 9 ng/ml) (red line).

FIGURE 5

Potential study designs in men with biochemical recurrent or metastatic prostate cancer to determine whether alternating BAT with androgen deprivation can improve survival parameters compared with androgen deprivation alone (Study Design 1) and to determine whether PSA provocation by BAT can be used to identify men who may benefit from the addition of more intensive hormonal therapy or chemotherapy as part of their first line regimen (Study Design 2). BAT, bipolar androgen therapy.