Phase 2/3 Trial Will Test BAT Followed by Darolutamide

A newly registered randomised phase 2/3trial will test an unusual strategy in metastatic androgen pathway modulation-resistant prostate cancer (mAPMR; formerly mCRPC or castration-resistant prostate cancer): deliberately exposing resistant cancer cells to very high testosterone levels before attacking the androgen receptor again with darolutamide.

The study plans to enrol 432 patients with mCRPC who have already progressed on an androgen receptor pathway inhibitor such as abiraterone, enzalutamide, apalutamide or darolutamide. Patients will be randomised either to standard sequential treatment or to Bipolar Androgen Therapy (BAT), using intramuscular testosterone every 28 days, followed at progression by darolutamide.

The important point is that BAT is not simply being tested as another treatment for mCRPC. The hypothesis is that prostate cancer adapts to long-term androgen deprivation partly by increasing its dependence on, and expression of, the androgen receptor. Suddenly exposing these highly adapted cells to supraphysiological testosterone may disrupt that state, induce DNA damage and cell-cycle stress, and potentially reverse some mechanisms of resistance. Subsequent intense androgen-receptor blockade may then become effective again.

There is already clinical evidence for this effect. In the randomised TRANSFORMER trial, BAT itself did not outperform enzalutamide: median progression-free survival was 5.7 months in both groups. However, the results after crossover were striking. Among patients receiving enzalutamide after BAT, 77.8% achieved a PSA decline of at least 50%, compared with roughly 25% when enzalutamide was used directly after abiraterone. Median PSA progression-free survival with enzalutamide increased from 3.8 to 10.9 months after BAT, while PFS2 reached 28.2 months with the BAT to enzalutamide sequence compared with 19.6 months for the reverse sequence.

The new trial has therefore chosen PFS2, progression after both treatments, as its primary phase 2 endpoint. This is critical: the investigators are testing the entire therapeutic sequence rather than asking whether BAT alone can outperform another mCRPC drug. If the BAT to darolutamide strategy shows sufficient improvement in PFS2, the study will continue into phase 3, where overall survival becomes the primary efficacy endpoint.

The control arm is also unusually demanding. Physicians can select standard treatment including docetaxel, abiraterone or enzalutamide initially, followed at progression by options including cabazitaxel, lutetium-177 PSMA therapy, chemotherapy or another androgen-receptor pathway treatment. BAT followed by darolutamide will therefore have to compete not against placebo or a weak comparator, but against two consecutive lines of currently available mCRPC treatment.

Another ongoing trial, WOMBAT, is already investigating the relationship between BAT and darolutamide in non-metastatic castration-resistant disease, using high-dose testosterone and intermittent darolutamide in patients progressing on the drug. Together, these studies are testing an increasingly intriguing concept: instead of continuously pushing prostate cancer in the same hormonal direction until resistance emerges, repeatedly forcing the tumour between opposite extremes of androgen signalling may make adaptation considerably more difficult.

Clinical trial.