Barcelona, Spain (UroToday.com) In this session, Dr. Elena Castro discussed four prostate cancer abstracts:
Dr. Castro began by reviewing that alterations in DNA damage repair (DDR) genes have been identified in approximately 20% of men with metastatic castration-resistant prostate cancer (mCRPC). The benefit of a synthetic lethality strategy with PARP inhibitors is being explored in several clinical trials. In parallel, there is a dedicated effort to identify the strongest molecular predictors of response. At this time, however, the clinical implications of many DDR alterations are unknown.
She moved on to discuss three clinical trials that are being reported at ESMO, highlighting differences in the specimens tested for DDR alterations, the panel of genes that were screened, and the genomic alterations required for inclusion in the studies.
In PROfound, a Phase 3 study of olaparib in patients with mCRPC with progression on Abiraterone or Enzalutamide, 4069 patient samples were sent for tissue analysis, of which 31% were not successfully sequenced. Reasons for failure included issues with pathology, DNA extraction, and sequencing failure. These findings highlight the importance of obtaining high-quality samples for genomic testing. Of the 61% of patients who successfully underwent tumor sequencing, 28% of sequenced samples (19.2% of submitted samples) were found to have a qualifying DDR alteration with BRCA2 being the most commonly mutated gene, consistent with prior reports.
In contrast, GALAHAD, a phase 2 study of niraparib in men with mCRPC, enrolled patients with bi-allelic DDR alterations detected in plasma. Of the patients screened, 7.8% contained an alteration that met the inclusion criteria.
Dr. Castro then compared objective and PSA response rates in the BRCA1/2 population across TRITON2 and GALAHAD. The overall response rate (ORR) in the two studies was similar (43.9% vs 41%), as was the PSA response (52.0% vs 50.0%).
Both somatic and germline DDR alterations are frequently observed in the mCRPC population. In the TRITON2 study, similar response rates were seen among patients with either type of alteration. She further highlighted that among patients with responded in the TRITON2 and GALAHAD study, approximately 50% of patients had a duration of response greater than 6 months. Unfortunately, some patients with DDR alterations in these studies did not respond, and Dr. Castro stressed the importance of identifying better molecular biomarkers to predict response to PARP inhibitors.
Moving on, she highlighted data that CDK12 alterations result in a distinct subset of advanced prostate cancers. In the abstract submitted by Antonarakis, 58 patients with mono- or bi-allelic CDK12 loss were identified and analyzed. These represented an aggressive cohort of patients with 79% having Gleason Grade 5 pattern and 47% having de novo metastatic disease. Generally, responses to therapy were poor, however, these patients seemed to have favorable responses to PD-1 inhibitors with 38% of patients responding. PSA responses to PARP inhibitors in CDK12 altered patients in TRITON2 (7.1%) and TOPARP-B (0%) were similarly low.
Dr. Castro concluded that rucaparib and niraparib have high and durable clinical activity in mCRPC patients with some DDR alterations after progression on various lines of therapy with particularly high rates of response in patients with BRCA1/2 alterations while CDK12 deficient tumors are unlikely to respond. Importantly, responses in BRCA1/2 patients seem to be independent of whether the alterations are germline vs somatic or mono- vs bi-allelic, though this will need further clarification. Additional strong predictive biomarkers beyond BRCA1/2 are needed. Overall, these findings support the implementation of tumor/plasma testing in routine clinical practice for patients with advanced prostate cancer. She ended by emphasizing that the field needs to work towards implementing genomic testing outside of clinical trials and academic medical centers, so that all patients can benefit from these advances.
Presented by: Elena Castro, MD, Ph.D., Medical Oncologist and Clinician Scientist at Spanish National Cancer Research Center, Madrid, Spain
Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain