New transcriptomic data from nearly 20,000 patients with localized prostate cancer reveal a previously uncharacterized subset of tumours that have low androgen receptor activity (ARA), biological and clinical similarities to metastatic castration-resistant prostate cancer (mCRPC) and specific sensitivities to systemic treatments.

The effects of varying ARA in men receiving systemic treatments for mCRPC are being extensively studied, but whether ARA is heterogeneous and has a role in outcomes in treatment-naive localized disease was unknown. In a new study, Spratt and colleagues first defined an ARA score and found that ~10% of tumours across the tested cohorts were classified as having low ARA. Gene expression and immunohistochemistry analyses showed that tumours with low ARA were more likely to be negative for expression of ERG, ETS and SPINK and to have a basal phenotype than those with high ARA. Furthermore, gene expression of low ARA tumours was increased for immune signalling and neuroendocrine markers but decreased for DNA repair pathway markers.

Evaluating whether this different phenotype had prognostic relevance, the team found that men with low ARA tumours had an increased potential for metastatic disease according to Decipher scores. This finding was validated using clinical data, demonstrating that low ARA was significantly associated with an increased risk of developing metastatic disease (HR 2.61, 95% CI 1.22–5.60; P = 0.01) in a multivariate competing risks regression analysis.

Finally, the researchers found that tumours with low ARA were significantly less likely to be sensitive to androgen deprivation therapy (OR 0.41, 95% CI 0.21–0.80; P = 0.008) and more likely to develop castration resistance than those with high ARA. Sensitivity scores of low ARA tumours were increased for platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors and decreased for docetaxel. Tumours with low ARA were also predicted to have increased potential for responses to radiotherapy.