AR null patients generally did not harbor AR gains at the genomic level as one might expect, and all cases with AR gain showed high levels of AR protein expression by IHC. A major caveat for defining AR indifference vs. AR positivity though has to do with whether the AR transcriptional program is on or off or altered, as we know that many patients with NEPC or small cell transformation can still express AR protein in their tumors but have low AR activity1 and low PSA secretion. Interestingly, TP53 and RB1 alterations were identified in patients with and without the AR null phenotype but were enriched in the AR null tumors, suggesting that patients with these alterations are at risk for loss of AR dependence. All AR null mCRPC patients had prior abiraterone or enzalutamide, suggesting divergent clonal evolution or epigenetic plasticity leading to loss of AR expression, accompanied by low PSA secretion.
In summary, these data suggest that loss of AR dependence may be suspected in patients with mCRPC following AR inhibition who lack genomic evidence of AR gain/amplification, and who have RB1/TP53 alterations, and many of these patients will have a high volume of disease, such as visceral metastases, without high PSA levels, similar to the MD Anderson “anaplastic” criteria.2,3 Such patients may benefit more from taxane or platinum-based chemotherapy. However, men with AR detectable and even AR amplified mCRPC may also have AR in different diseases, and this is a major caveat of this paper and for AR-directed novel therapies. Having a biomarker for AR activity rather than just expression, reflecting the activity of either full length or AR variants, may be much more relevant for identifying patients likely to benefit from AR pathway inhibitors as compared to those men where the AR has been bypassed.
Written by: Andrew John Armstrong, MD, Professor of Medicine, Associate Professor in Pharmacology and Cancer Biology, Professor in Surgery, Department of Medicine, Duke University School of Medicine
- Aggarwal R, Huang J, Alumkal J, et al. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol. 2018; 36(24):2492-2503.
- Aparicio A, Harzstark A, Corn P, et al., Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer Volume Clin Cancer Res. 2013;19(13); 3621–30.
- Corn B, Feldman D, Wexler I, et al., The science of hope. Lancet Oncol. 2020; 21(9): E452-E459