SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic...

Area of Science:

• Oncology
• Genetics
• Clinical Trials

Background:

• Current standard of care for metastatic castration-sensitive prostate cancer (mCSPC) involves intensifying androgen deprivation therapy (ADT) with docetaxel or androgen receptor axis-targeted therapies (ARAT).
• Biomarkers for guiding treatment selection in mCSPC are currently lacking.
• SPOP mutations are found in a subset of prostate cancer patients.

Purpose of the Study:

• To investigate if SPOP mutations can serve as a predictive biomarker for treatment response in de novo metastatic castration-sensitive prostate cancer (dn-mCSPC).
• To compare the efficacy of ADT intensification with ARAT versus docetaxel in patients with and without SPOP mutations.

Main Methods:

• Analysis of patient-level data from a U.S. prostate cancer clinico-genomic database (2011-2021).
• Inclusion criteria: metastatic disease diagnosis, genomic profiling, and initiation of ARAT or docetaxel within specified timeframes.
• Statistical comparison of time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) using log-rank tests and Cox proportional hazards models.

Main Results:

• In the ARAT cohort, SPOP mutations were associated with significantly longer TTCRPC (not reached vs. 16.7 months) and OS (not reached vs. 27.2 months).
• In contrast, SPOP mutation status did not correlate with TTCRPC or OS in the docetaxel-treated cohort.
• Adjusted hazard ratios indicated a protective effect of SPOP mutations with ARAT (aHR for TTCRPC: 0.20, aHR for OS: 0.19).

Conclusions:

• SPOP mutations are associated with improved outcomes when treated with ADT plus ARAT in real-world settings for dn-mCSPC patients.
• SPOP mutation status does not appear to predict outcomes for patients treated with ADT plus docetaxel.
• SPOP mutations may function as a predictive biomarker to guide treatment selection in mCSPC.