Background: Inactivating missense mutations in the tumor suppressor gene speckle-type POZ (SPOP) increase the transcriptional activity of the androgen receptor (AR) and sensitivity to hormonal therapies in men with hormone sensitive prostate cancer. Data is more limited in the castration-resistant prostate cancer (CRPC) setting. In the AbiRace and PANTHER trials, Black men with metastatic CRPC who received abiraterone +/- apalutamide had improved outcomes suggesting ancestry-based differences in the benefits of single or dual AR pathway inhibitor (ARPI) therapy. While Black patients are more likely to have SPOP mutations, we hypothesized that Black men have improved outcomes with potent AR inhibition irrespective of an SPOP mutation.

Methods: This retrospective cohort contains 301 patients: 223 SPOP wild-type (wt) control patients and enriched in 78 SPOP-mutated (m) patients who received an ARPI in the CRPC setting, with no prior ARPI use. All patients had somatic gene profiling via Tempus xT (solid-tumor) or xF (liquid biopsy) NGS assays. The primary objective was to describe clinical outcomes by race and SPOPm status. PSA declines (>30, >50, >90% PSA decline from baseline) by SPOP status were compared using logistic regression, and progression-free survival (PFS) and overall survival were tested using Cox proportional hazards models.

Results: This cohort was comprised of men with CRPC: 11% (n=34/301) were Black, 50% (n=150/301) were White, 5% (n=15/301) were of other races, and 34% were missing race data (102/301). SPOP mutations were identified in 32% of Black men (n=11/34) and 20% of White men (n=30/150). SPOPm patients had more bone (64 vs 45%) and visceral (14 vs 3%) metastases and more Gleason ≥8 disease (86 vs 68%). Median pre-ARPI PSAs were also higher in the SPOPm vs SPOPwt group: 15 ng/mL vs 8 ng/mL. After adjusting for race, visceral mets, and PSA, there was no significant difference in PFS (HR 0.78, 95% 0.56-1.07, p=0.12) or overall survival (HR 0.79, 95% 0.54-1.16, p=0.2) by SPOP status. Black men had improved OS (HR 0.44 p=0.007) irrespective of SPOP status. However, PSA declines were more commonly observed and deeper after ARPI therapy in SPOPm carriers (Table).

Conclusions: In this exploratory analysis, patients with SPOP mutations demonstrated greater PSA declines with an ARPI in the CRPC setting compared to SPOPwt patients but SPOP mutations did not explain the race-survival disparity. Larger data sets with greater diversity are needed to examine SPOP and other ancestral-associated genomic alterations associated with race and outcomes in CRPC patients treated with an ARPI.

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