Genomic, clinical characteristics, and treatment outcomes of patients with metastatic castration-sensitive prostate cancer with SPOP mutations: Analysis from the Kaiser Permanente Northern California Healthcare System.
Authors: Thomas Sachdev P. , Arora Amit , Huang Hui X. , Jiang Chen , Chung Elaine , Suga Jennifer Marie , Sundaresan Tilak Kumar , Truong Thach-Giao , Pan Minggui , Harzstark Andrea 
Published: March 2023

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Background: Androgen deprivation therapy (ADT) plus either Abiraterone, Docetaxel or Enzalutamide (ADE) improves overall survival (OS) of men with metastatic M1 castrate-sensitive prostate cancer (mCSPC), compared to ADT alone and is currently standard of care. Men with mCSPC with a point mutation of the speckle-type pox virus and zinc finger mutation (mutSPOP) derive superior response to ADT compared to wild type SPOP. The additive benefit of ADE to ADT in this subclass of CSPC is unclear. We sought to evaluate the benefit of therapy in patients with mutSPOP in a real-world setting. Methods: Between November 2017 and July 2022, 1002, patients in the Kaiser Permanente Northern California (KPNC) health system with advanced prostate cancer had tumor specimens examined by next generation sequencing (NGS). Of these patients, we retrospectively identified 70 mCSPC patients with mutSPOP. Patient records were reviewed to determine baseline characteristics, therapy for CSPC, subsequent therapy for Castrate Resistant Prostate Cancer (CRPC), and clinical outcome. The primary outcome was progression-free survival (PFS) for patients who received ADT alone or ADT plus ADE. PFS was defined as time to either PSA progression by PCWG2 criteria, clinical progression, or time to next line of therapy. Results: Median age for the 70 patients with mutSPOP was 75 years (range 50-91). Thirty-six (51%) were non-Hispanic white; 11 (16%) were African American; and 13 (19%) were Asian. F133 was the most frequently mutated allele (64%), TP53 was the most common co-mutated gene (27%), and mutations in MSH2, MSH6 and BRCA1 were identified in one patient each. Two patients had concurrent ERG fusion. Thirty-six patients (51%) had a Gleason score 8-10 and 48 (69%) were diagnosed with de-novo metastatic disease. Twenty-seven patients (39%) received ADT alone, 41 (59%) received ADT + ADE, 2 patients elected observation only. PFS was 28.1 months (mos) for ADT alone vs 35 for ADT+ADE (p=0.08). Twenty-nine patients (41%) received 2nd line therapy at CRPC; among them 24 received ADT plus Abiraterone or Enzalutamide. Median PFS for all the CRPC patients who received 2nd line treatment was 15mos. Median PFS for CRPC patients who received 2nd line treatment with Abiraterone, or Enzalutamide was 15.3 mos. Median overall survival for the entire group was 173 mos (95% CI 135-NR). Conclusions: In this real-world study within KPNC, we confirmed the durable benefit of ADT based therapy in patients with mutSPOP. Patients with mutSPOP derived similar benefit regardless of 1st line therapy (ADT vs ADT + ADE). We also noted durable responses to abiraterone or enzalutamide for CRPC after initial treatment with ADE for CSPC. Confirmation of these findings from an another large NGS database is ongoing and will be reported later.