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
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