ASCO GU 2020: Response to Olaparib or Carboplatin in a Real-World Cohort of Men with DNA Damage Repair DDR Deficient Metastatic Castration-Resistant Prostate Cancer (mCRPC)

San Francisco, CA ( PARP inhibitors and platinum chemotherapy cause synthetic lethality and result in clinical benefit in men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor deleterious alterations in DDR genes. BRCA2 is the strongest predictor for response to PARP inhibitors, but data supports a role for BRCA1, ATM, and other genes as potentially deriving a benefit from treatment. PARPi are more expensive than platinum chemotherapy, but whether they are more effective is not known. A the prostate cancer session at GU ASCO 2020, Dr. Jacob Berchuck and colleagues presented results of their evaluation of outcomes in men with DDR-deficient mCRPC treated with PARP inhibitors or platinum chemotherapy.

This study identified men treated at the Dana-Farber Cancer Institute who received olaparib or carboplatin for mCRPC and underwent tumor mutation profiling. Outcomes were assessed by mutation status in the following genes: ATM, ATRX, BRCA1, BRIP1, CHEK2, FANCA, FANCF, FANCG, NBN, PALB2, and WRN. Progression-free survival (PFS) was determined using Prostate Cancer Working Group 3 guidelines. Pathogenic germline or somatic single-nucleotide variants, insertions/deletions, and copy number loss in BRCA2, BRCA1, and ATM, were identified. The log-rank test was utilized to compare differences in PFS and PSA response was determined as >=50% decrease on-treatment PSA compared to baseline PSA.

The investigators identified 23 men who received olaparib of which 69.6% received prior taxane chemotherapy and 4.3% prior carboplatin. There were 34 men treated with carboplatin of which 91.2% received carboplatin in combination with a taxane, 88.2% received prior taxane chemotherapy, and 8.8% prior PARP inhibitor therapy. Among men with BRCA2 alterations by mutation status, there was a significant difference in PFS between those treated with olaparib versus carboplatin.

ASCO GU 2020 BRCA2 alterations

There was no difference in PFS observed among men with all DDR genes by mutation status treated with olaparib versus carboplatin:

ASCO GU 2020 DDR genes by mutation status

The following figure demonstrates the best PSA response for olaparib and carboplatin by mutation status:

ASCO GU 2020 all DDR genes
The study is limited by the small sample size of both the PARP inhibitor and chemotherapy arms.

Dr. Berchuck concluded with several take-home messages:

  • Olaparib and carboplatin are associated with longer PFS and higher rates of PSA response in men with CRPC whose tumors harbor BRCA2 alterations compared to those without BRCA2 mutations
  • Olaparib is associated with longer PFS than carboplatin in men with mCRPC whose tumors harbor DDR alterations
  • Exceptional responses (>18 months) are observed in BRCA2-altered patients treated with olaparib
  • Some patients with no DDR alterations experience excellent responses (>12 months) to olaparib and carboplatin highlighting the need for further research to identify predictive biomarkers in mCRPC
Presented by: Jacob Berchuck, MD, Dana Farber Cancer Institute, Boston, Massachusetts 

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md 
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