Phase 2 ExBAT Trial: AR Amplification Linked to Poorer Outcomes With Alternating Testosterone and Darolutamide

New biomarker findings from the phase 2 ExBAT trial, suggest that androgen receptor (AR) amplification may be associated with poorer outcomes in patients receiving alternating bipolar androgen therapy (BAT) and darolutamide for metastatic castration-resistant prostate cancer (mCRPC).

ExBAT/LACOG 0620 investigated an experimental strategy combining periods of supraphysiological testosterone exposure with subsequent androgen receptor inhibition. Patients whose disease had progressed on abiraterone received testosterone cypionate followed by darolutamide in repeated 63-day cycles, with the aim of exploiting changes in androgen receptor signaling and potentially restoring sensitivity to hormonal treatment.

The trial previously demonstrated encouraging clinical activity, with 41.3% of patients remaining free from radiographic progression at 12 months and a median radiographic progression-free survival (rPFS) of 8.1 months.

The new exploratory analysis examined circulating tumor DNA (ctDNA) from 46 patients to determine whether specific genetic alterations could help identify those more likely to experience durable disease control.

AR alterations were detected in 14 patients (30.4%) and were associated with significantly worse overall survival. Patients with AR alterations had a median overall survival of 12.3 months, compared with a median not yet reached among those without these alterations. Radiographic progression-free survival was also numerically shorter, at 5.8 versus 11.9 months, although this difference was not statistically significant.

AR amplification appeared to be the strongest contributor to these differences. Among the eight patients with AR amplification, the 12-month overall survival rate was 50%, compared with 88.9% among patients without amplification.

Similarly, the proportion remaining free from radiographic progression at 12 months was 20.8% in patients with AR amplification, compared with 47.5% in those without it. This difference approached but did not reach conventional statistical significance .

By contrast, AR mutations without amplification were not significantly associated with either radiographic progression-free survival or overall survival.

The researchers also explored alterations involving TP53, PTEN, and RB1. Patients with double-hit alterations affecting these genes showed numerically longer median rPFS (9.1 versus 4.1 months), but the difference was not statistically significant and should be regarded as exploratory.

These findings are particularly interesting because AR amplification is a recognized mechanism of resistance to androgen receptor pathway inhibitors. The results raise the possibility that the underlying molecular characteristics of the tumor may influence outcomes during treatment strategies alternating supraphysiological testosterone with potent androgen receptor blockade.

However, the findings do not establish that AR amplification specifically causes resistance to ExBAT. The study was small, non-randomized, and conducted without a control group. Consequently, AR amplification could represent a general marker of more aggressive disease rather than a biomarker specifically predicting reduced benefit from this treatment strategy.

The very small number of patients with AR amplification also limits the precision and generalizability of the findings. Furthermore, the analysis was exploratory, and prospective validation will be necessary before ctDNA-based AR testing can be used to guide treatment selection.

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