Many studies have evaluated the predictive and prognostic significance of DDR alterations in prostate cancer. The most robust data is for germline BRCA2 alteration, which appears to be a negative prognostic factor, associated with worse prostate cancer-specific survival compared to non-carriers. Germline BRCA2 carriers also have a shorter time from continuous ADT to mCRPC and shorter survival from diagnosis with mCRPC. The data is less clear for other germline alterations, although this is limited by most studies grouping non-BRCA2 genes into one group. The predictive value of germline DDR alterations to standard prostate cancer therapies is also not clear as multiple studies show conflicting results.
It’s clear that somatic and germline DDR alterations do predict response to PARP inhibitors. Four studies have evaluated response to PARP inhibitors: PROFOUND, TRITON2, TALAPRO-1, and GALAHAD. Each study evaluated a different PARP inhibitor and there were significant differences in the primary objective, specimen tested for DDR alterations, the genomic test used, genes screened, and genomic alteration required for eligibility highlighted in the slide below.
PROFOUND was a randomized phase III trial of olaparib versus physician’s choice presented at ESMO 2019, which showed a significant improvement in radiographic progression-free survival for olaparib in men with ATM, BRCA1, and BRCA2 alterations. The exploratory gene-by-gene analysis showed better responses for certain genes (BRCA2, RAD51B, RAD54L) than others (ATM, BRCA1).
Preliminary data from TRITON2 (rucaparib) and GALAHAD (niraparib) show high objective response rates (~40%) and PSA response rates (~50%) in men with BRCA2 alterations. Further, responses can be durable, as long as two years, and are irrespective of whether men had somatic versus germline or mono-allelic versus bi-allelic alterations in these two studies. Conversely, patients with non-BRCA2 alterations in these two studies had poorer objective response rates (10-15%) and PSA response rates (3-10%).
There is a significant interest in which DDR genes predict response to PARP inhibitors. Across TRITON2, TOPARP-B, and PROFOUND, there is concordant data suggesting that objective response rates (~9%) and PSA response rates (3-5%) are low in men with ATM alterations. Similar results are seen for CDK12, although emerging data suggest that men with CDK12 alterations may be candidates for checkpoint immunotherapy.
Mismatch repair (MMR) gene alterations and patients with high microsatellite instability (MSI-H) are known to respond to immune checkpoint inhibitors in other solid tumors. Recent data from Dr. Wassim Abida at Memorial Sloan Kettering Cancer Center demonstrated high response rates to checkpoint immunotherapy in men with mCRPC whose tumors harbor MMR gene alterations and/or MSI-H.
Dr. Castro then discussed how to test for DDR alterations: primary tumor or metastatic biopsy, tissue or circulating tumor DNA (ctDNA), germline or somatic. Emerging data suggest that DDR alterations tend to be truncal events that occur early in prostate cancer tumorigenesis. Further, with the primary tumor often being easier to perform molecular testing on than small metastatic needle biopsies, Dr. Castro condoned molecular testing on the primary prostate tissue.
Given high tissue failure test rates (30% in the PRODUND and TRITON2 trials), ctDNA is an attractive non-invasive way for identifying alterations in DDR genes. ctDNA has been demonstrated to have high concordance with tumor tissue for detecting DDR alterations, however, she cautioned that copy number alteration calling is poor when ctDNA fraction is less than 30%.
Dr. Castro concluded by discussing the pros and cons of germline versus somatic testing. Pros of germline testing is that it’s cheap and accessible, however, it will miss 10-15% of men with somatic DDR alterations who would be eligible for PARP inhibitor therapy. There are additional implications for germline testing. If a germline DDR alteration is identified, men should be referred to genetic counseling. Through cascade testing of affected men’s family members.
Dr. Castro concluded by discussing the pros and cons of germline versus somatic testing. Pros of germline testing is that it’s cheap and accessible, however, it will miss 10-15% of men with somatic DDR alterations who would be eligible for PARP inhibitor therapy. There are additional implications for germline testing. If a germline DDR alteration is identified, men should be referred to genetic counseling. Through cascade testing of affected men’s family members there is an opportunity for early detection and risk reduction for other DDR-associated cancers. Somatic testing detects most DDR alterations, but it is expensive, and germline alterations can be missed as acquired changes in the tumor can mask the germline alteration.
Presented by: Elena Castro, MD, PhD, Medical Oncologist and Clinician Scientist at Spanish National Cancer Research Center, Madrid, SpainWritten by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California