2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

Co-Occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer - Beyond The Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA2-mutant cancers are the foremost example of synthetic lethality in prostate cancer. Synthetic lethality is the therapeutic exploitation of a genetic mutation that leads to the death of cancer cells. In BRCA2-altered prostate cancers, the cellular machinery mediating double-strand DNA break repair shifts to rely on PARP enzymes.

Thus, PARP inhibitors like olaparib lead to faulty DNA repair and cancer cell death. Response rates for PARP inhibitors in BRCA2-deficient cancers are around 40-60%, which is clinically meaningful. However, response rates for other common mutations such as BRCA1 (30%) and ATM (10%) are less impressive. Thus, a better appreciation of clinical states that confer enhanced susceptibility to PARP inhibitors will help us better implement the synthetic lethality paradigm in clinical practice.

In this study, we generated several important new findings concerning PARP inhibitor susceptibility in BRCA2-mutated prostate cancer. First, we found that co-mutation of both SPOP and BRCA2 predicted a significantly better response rate (86%) to PARP inhibitors than BRCA2 mutation alone. This further translated into significantly improving overall survival for patients with cancers carrying both mutations (adjusted HR 0.19). Second, we found that this improved overall survival in BRCA2/SPOP co-altered cancers was not shared in patients receiving other therapies in this setting, meaning that it is probably specific to PARP inhibition. Third, we found that a molecular signature of homologous recombination defects (HRD) is indeed predicted by SPOP/BRCA2 co-mutation and may thus help identify patients with other mutation combinations who will benefit from PARP inhibitor treatment.

Overall, this study highlights synthetic lethality as a highly promising treatment paradigm that can be exploited in patients with SPOP-mutant cancers (representing 10% of prostate cancer). For these SPOP-altered patients, we have promising ongoing trials at the Mayo Clinic of both PARP inhibition (NCT05689021) and ATR inhibition (NCT05828082) to implement the synthetic lethality paradigm in SPOP-mutant castration-resistant prostate cancer.

Written by: Emmanuel Antonarakis, MD1 & Jacob Orme, MD, PhD2

  1. Clark Endowed Professor of Medicine, Division of Hematology, Oncology and Transplantation, Associate Director of Translational Research, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
  2. Oncologist, Mayo Clinic, Rochester, MN
Read the Abstract 

Related Content:

Novel Biomarker Analysis Reveals SPOP Gene Mutation Unlocks Sensitivity to PARP Inhibitor Treatment in Metastatic Castration-Resistant Prostate Cancer - Emmanuel Antonarakis & Jacob Orme