San Diego, CA USA (UroToday.com) Emmanuel Antonarakis discussed biomarkers of resistance and therapeutic implications in today’s society of basic urologic research meeting at the 2016 AUA. Some patients respond to abiraterone (abi) and enzalutamide (enza), some respond to a single agent, and approximately 10% have resistance to both. It is thus vital to identify any shared mechanisms to resistance.
In 2016 there were 50 review articles on AR resistance, and in general, 3 categories were identified: reactivation of AR itself (increasing ligand by intratumoral synthesis, AR splice variants, AR agonistic point mutations), AR bypass (another steroid receptor hijacks the response), and AR independent mechanisms.
Resistance to abi is associated with upregulation of Cyp17 and AR, glucocorticoid activated AR mutations, progesterone activated AR mutations, and splice variants. Resistance to enza is associated with upregulation of AR, Enza-activated AR mutations, induction of GR expression, AR splice variants, and androgen-independent/ AR-independent mechanisms.
In the setting of AR splice variants, a truncated AR is missing its ligand binding domain. Transcription factors remain active as ligand independent transcription entities. In CTC studies it was demonstrated that if AR variant was present, this conferred resistance to abi/enza. PFS and OS were inferior in those with the variant present. AR-V7 has been identified as the strongest predictor of survival.
Based on this, Dr. Antonarakis presented a potential decision tree: AR-V7 positive patients should get docetaxel first, and if recurrence is identified, AR-V7 should be rechecked, as there have been cases of Arv7 status changing after treatment. Those that remain positive should get cabazitaxel, and those that revert to AR-V7 negative should get abi/enza. Those who are initially AR-V7 negative should start with abi/enza, and upon recurrence should have AR-V7 status rechecked. Those who are positive should then proceed with chemotherapy while AR-V7 negative patients should switch AR inhibitors.
Ultimately, we should focus our research efforts on a blood-based test that can comprehensively detect the full complement of AR anomalies. In the setting of wild-type AR only (no amplification, mutation, or splice variants), the approach would entail conventional AR-directed treatment. Those with aberrant AR-driven mutations should receive next generation AR-directed treatment, while AR-independent patients whould receive alternatives such as taxane, immunotherapy, or radium 223 vs clinical trial enrollment. Dr. Antonarakis concluded that future trial design can be based on biomarker selection (i.e. those with aberrant AR are randomized to receive enza, abi/enza, or enza/taxane) or biomarker stratification (i.e. patients are stratified by canonical AR, aberrant AR, or AR-null status).
Presented By: Emmanuel Antonarakis, MD
Written By: Nikhil Waingankar, MD; Fox Chase Cancer Center, Philadelphia, PA., at the 2016 AUA Annual Meeting - May 6 - 10, 2016 – San Diego, California, USA
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