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

Abstract

Introduction: 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. Methods: Patient-level data from a de-identified nationwide (US-based) prostate cancer clinico-genomic database (CGDB) between January 2011- 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 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. Results: 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. Conclusions: 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.

Abigene, a Prospective, Multicentric Study of Abiraterone Acetate Pharmacogenetics in Metastatic Castration-Resistant Prostate Cancer

“…A significant place is given to biomolecular alterations, including genes affecting tumor progression. In this respect, the recent study by Swami and coworkers [ 26 ] is particularly illustrative. The authors reported that SPOP mutations (an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex) were associated with improved outcomes in patients under AA treatment.…”

Molecular features and race‐associated outcomes of SPOP‐mutant metastatic castration‐resistant prostate cancer

“…Furthermore, we included patients receiving DTX at any line of treatment, which included patients who failed three or more previous lines of therapy. A recent study in de novo metastatic castration‐sensitive patients showed that OS and time to castration resistance were similar in SPOP ‐mut and SPOP ‐WT patients treated with DTX 14 . Since the study focused on castration‐sensitive patients, analysis of a larger cohort of mCRPC patients would be needed for evaluating SPOP status as a molecular marker to guide therapy selection for patients who failed prior ARSI.…”

“…A recent study in de novo metastatic castration-sensitive patients showed that OS and time to castration resistance were similar in SPOP-mut and SPOP-WT patients treated with DTX. 14 Since the study focused on castration-sensitive patients, analysis of a larger cohort of mCRPC patients would be needed for evaluating SPOP status as a molecular marker to guide therapy selection for patients who failed prior ARSI. These patients are often given DTX as the next line of therapy; however, if SPOP-mut is found to be associated with better Unique to this study was that the majority of patients were AA (59%).…”

Highlighting recent progress in the treatment of men with advanced prostate cancer

“…A variety of genomic markers have been identified that may help predict responses to treatments for mHSPC, but how exactly to incorporate these genomic predictors into decisions regarding doublet versus triplet therapy is unclear. Androgen receptor splice variant 7 protein expression has been linked to shorter responses to ADT in men with mHSPC, whereas inactivating mutations in the SPOP gene have been linked to improved outcomes with ARAT agents but not docetaxel [7,8]. The presence of DNA repair defects has been linked to more rapid development of castration resistance with ADT as has the presence of high baseline levels of circulating tumor cells [9,10].…”