Emmanuel S. Antonarakis, MD, presented “Castration Resistant Prostate Cancer – Developments and Challenges from 2020” for the Grand Rounds in Urology audience in March 2021.
How to cite: Antonarakis, Emmanuel S. “Castration Resistant Prostate Cancer – Developments and Challenges from 2020” March 2021. Accessed Nov 2024. https://grandroundsinurology.com/castration-resistant-prostate-cancer-developments-and-challenges-from-2020/
Castration Resistant Prostate Cancer – Developments and Challenges from 2020: Summary
In this Platinum Lecture, Emmanuel S. Antonarakis, MD, Professor of Oncology and Urology as well as Director of Prostate Cancer Medical Oncology Research and the Co-Director of the Prostate Cancer Multidisciplinary Clinic at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, summarizes developments from 2020 in mutation-targeted treatments for metastatic castration-resistant prostate cancer (mCRPC).
He begins by looking at the successes of PARP inhibitors for homologous recombination repair (HRR)-mutated mCRPC. Dr. Antonarakis explains that 23% of metastatic castration-resistant prostate cancers harbor somatic DNA repair alterations and 12% of patients with metastatic prostate cancer have a germline DNA repair defect, and that either kind of mutation can theoretically make a patient eligible for treatment with PARP inhibitors. The FDA approved both olaparib and rucaparib in May 2020 for patients with mCRPC, based on the results of the PROfound and the TRITON2 studies, respectively. TRITON2 was only a phase 2 trial, and TRITON3 is currently underway to get rucaparib full approval. Researchers are also looking at other PARP inhibitors called niraparib and talazoparib. Patients with any HRR mutation are eligible for olaparib, and patients with BRCA mutations are eligible for rucaparib, but Dr. Antonarakis notes that meta-analysis shows that these PARP inhibitors, as well as niraparib and talazoparib only have a significant positive impact on patients with the BRCA2 mutation. In the second part of the presentation, Dr. Antonarakis considers the challenges presented by PD1 inhibitors for mCRPC. He observes that the KeyNote-199 study of pembrolizumab for mCRPC saw very low response rates, and that while the CheckMate-650 study of nivolumab plus ipilimumab saw higher response rates, it also saw very high toxicity rates. Patients with deficient mismatch repair (dMMR) prostate cancers respond to PD1 inhibitors, but the response is not long-lasting.
Dr. Antonarakis suggests that the real challenge is that not many patients with prostate cancer have the kinds of mutations that respond to PD1 inhibition, and he suggests that there is more promise in research into different molecular targets such as B7-H3 or PSMA. The talk concludes with a Q&A during which Dr. Antonarakis discusses radioligands and the ideal time to perform germline testing.
Dr. Antonarakis’ disclosures:
- Consultant/Advisor for: Janssen, Astellas, Sanofi, Dendreon, Bayer, BMS, Amgen, ESSA, Constellation, Blue Earth, Exact Sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis, Eli Lilly.
- Grant/Research support from: Janssen, J&J, Sanofi, BMS, Pfizer, AstraZeneca, Novartis, Curium, Constellation, ESSA, Celgene, Merck, Bayer, Clovis.
- Inventions/Patents: Co-inventor of an AR-V7 technology licensed to Qiagen.
ABOUT THE AUTHOR
Dr. Antonarakis is Associate Director for Translational Research at the University of Minnesota Medical School Masonic Cancer Center, as well as the Clark Endowed Professor of Medicine and Director of Genitourinary Oncology in the Department of Medicine’s Division of Hematology, Oncology, and Transplantation (HOT). He was formerly a Professor of Oncology and Urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, as well as the Director of Prostate Cancer Medical Oncology Research and the Co-Director of the Prostate Cancer Multi-Disciplinary Clinic there. He graduated from the University of Wales College of Medicine (United Kingdom) in 2003, and then completed a Residency in Internal Medicine at the Johns Hopkins Bayview Medical Center, followed by a Fellowship in Medical Oncology at the Johns Hopkins Hospital. Since 2010, he has been on the Johns Hopkins faculty as an attending physician and translational researcher in the Department of Oncology. Dr Antonarakis’ clinical interest is the management of prostate cancer and other genitourinary malignancies.
His research focuses on drug development and clinical trial design for patients with prostate cancer, as well as cancer genomics. More specifically, he is interested in developing novel androgen-directed therapies, genetically-targeted therapies, and immunotherapies for men with recurrent or advanced prostate cancer, and using germline and cancer genomics to inform precision oncology approaches. He also has an interest in liquid biomarker development, specifically the clinical validation of the AR-V7 marker as well as DNA repair markers and their therapeutic implications. He is currently the PI of several phase II and III prostate cancer trials, and is an active member of the Prostate Cancer Clinical Trials Consortium (PCCTC) and the Eastern Cooperative Oncology Group (ECOG-ACRIN), as well as the NCI Prostate Cancer Task Force and the NCCN Prostate Cancer Panel. He serves on the editorial boards of several oncology journals, including the Journal of Clinical Oncology. He is the author of >290 peer-reviewed articles and several book chapters, and has edited a textbook about AR signaling in cancer.
