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SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic
Umang Swami1, Ryon P Graf2, Roberto H Nussenzveig1
1Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Purpose:
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 patients with de novo (dn)-mCSPC harboring SPOP mutations.
Experimental Design:
Patient-level data from a deidentified nationwide (U.S.-based) prostate cancer clinico-genomic database between January 2011 and December 2021 were extracted. Eligibility criteria: 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 hazards 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.
Results:
In the ARAT cohort, presence of SPOP mutation compared with wild-type was associated with more favorable TTCRPC [not reached (NR) vs. 16.7 months; adjusted HR (aHR), 0.20; 95% confidence interval (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.
Conclusions:
In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in patients with dn-mCSPC. This may serve as a predictive biomarker to guide treatment selection for patients with mCSPC.
Insights
SPOP mutations predict better outcomes for metastatic castration-sensitive prostate cancer patients treated with androgen receptor axis-targeted therapies (ARAT) but not docetaxel. This finding may guide treatment selection for advanced prostate cancer.
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.
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