SPOP mutations as a Predictive Biomarker for Androgen Receptor-Axis-Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer.

Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor-axis-targeted therapies (ARAT) are the current standard-of-care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in de novo (dn)-mCSPC patients harboring SPOP mutations.

Patient-level data from a de-identified nationwide (US-based) prostate cancer clinico-genomic database (CGDB) between January 2011- December 2021 were extracted.

diagnosis of metastatic disease within 30 days of original prostate cancer diagnosis, genomic profiling of a tissue biopsy collected within 90 days of original diagnosis, and initiation of ARAT or docetaxel within 120 days of initial diagnosis. The log-rank test and Cox proportional hazard models were used to compare time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for patients with and without SPOP mutations undergoing ADT intensification with ARAT or docetaxel.

In the ARAT cohort, presence of SPOP mutation compared to wild-type was associated with more favorable TTCRPC (not reached (NR) vs. 16.7 months, adjusted HR (aHR) 0.20; 95% CI 0.06-0.63; p=0.006) and OS (NR vs. 27.2 months, aHR 0.19; 95% CI 0.05-0.79; p=0.022). In contrast, SPOP mutation status was not associated with TTCRPC or OS in docetaxel-treated cohort.

In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in dn-mCSPC patients. This may serve as a predictive biomarker to guide treatment selection for mCSPC patients.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Sep 11 [Epub ahead of print]

Umang Swami, Ryon P Graf, Roberto H Nussenzveig, Virginia Fisher, Hanna Tukachinsky, Alexa B Schrock, Gerald Li, Jeffrey S Ross, Nicolas Sayegh, Nishita Tripathi, Vinay Mathew Thomas, Geoffrey R Oxnard, Emmanuel S Antonarakis, Neeraj Agarwal

University of Utah/Huntsman Cancer Institute, Salt lake City, UT, United States., Foundation Medicine, San Diego, CA, United States., University of Utah/Huntsman Cancer Institute, Salt Lake City, UT, United States., Foundation Medicine, Inc., Cambridge, MA, United States., Foundation Medicine Inc., Cambridge, MA, United States., Upstate Medical University, Syracuse, NY, United States., Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, Utah, United States., Foundation Medicine, Cambridge, United States., University of Minnesota, Minneapolis, United States.

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