From the Desk of the Associate Editor: Progression on Enzalutamide: Data from the PREVAIL Trial

Enzalutamide is a second generation AR inhibitor that engages AR through the ligand binding domain, inhibiting DNA binding and AR activity. In the PREVAIL study, enzalutamide improved overall survival in chemotherapy na├»ve men with mCRPC, and enzalutamide is presently a standard of care for these men, with greater activity observed when used prior to docetaxel as compared to following docetaxel.  While most men respond to enzalutamide in this setting, all men develop treatment resistance between 1-3 years. This present article explores how men progress on enzalutamide, using data from the PREVAIL trial.

The authors examined whether patients who progress without a rising PSA may have more aggressive and fatal disease, indicating possible lineage plasticity and loss of AR dependence, as compared to men who progress with a rising PSA as the first sign of progression.  Most men treated with enzalutamide progress with a rising PSA, but a minority 7.5% subset of patients developed radiographic progression without substantial PSA rises using PCWG2 criteria.  Most men who had radiographic progression on enzalutamide also had a rising PSA, indicating persistent AR activity to some degree.  

The Notable fndings from this post-hoc exploratory analysis was that
1) baseline pre-treatment characteristics could not predict non-rising PSA radiographic progression, as while patients with visceral metastases more commonly had a non-rising PSA, there was no statistical difference in the type of progression over time  

2) PSA-radiographic discordances were seen commonly with visceral metastases (34%) and bone (20%), indicating a subset of men with low PSA producing tumors that may differ by the pattern of spread

3) Of men with bone only metastases at baseline, 40% of men developed soft tissue progression over time

4) Surprisingly, there was no difference in overall survival between men who had radiographic progression on enzalutamide with a non-rising PSA and those who progressed with a rising PSA.  But really, this analysis had very few mortality events in this subgroup, limiting the ability to draw definitive conclusions here. We know that men with more anaplastic or neuroendocrine variants have aggressive disease and a poor prognosis, and our ability to see this transformation is limited by the data available and follow up available in this study.

The take home message is that there are frequent disconnects between PSA and imaging over time during AR therapy in men with mCRPC, illustrating the need for both bone and soft tissue imaging over time.  CT/MRI and bone scans are recommended periodically during enzalutamide therapy in order to fully understand the overall benefits and decisions around the need to change therapy over time, and I recommend imaging every 8-12 weeks initially for the first 6 months, then every 3 months in otherwise responding patients. More research is needed to characterize those men with AR indifferent cancers that do not produce PSA, and best to treat these men, such as chemotherapy and alternative approaches.

Written by: Andrew Armstrong, MD, ScM, FACP, USA

Dr. Armstrong is Associate Professor of Medicine, Surgery, Pharmacology and Cancer Biology and Associate Director of the Duke Cancer Institute Genitourinary Clinical Research Program. He is a medical oncologist and internationally recognized expert in experimental therapeutics and biomarker development in genitourinary cancers, particularly in prostate cancer

Read the PCAN Full Text Article Radiographic Progression with Non Rising PSA in mCRPC: PREVAIL
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