ASCO GU 2018: A Phase 2 Study of Olaparib and Durvalumab in mCRPC in an Unselected Population

San Francisco, CA (UroToday.com)  Dr. Fatima Karzai provided results of a phase 2 study assessing the addition of durvalumab to olaparib for men with mCRPC at today’s prostate cancer. Previous studies suggest 25-30% of sporadic mCRPC has defects in DNA repair pathways which may confer sensitivity to PARP inhibition (PARPi) [1,2]. Furthermore, immune checkpoint blockade may increase the proportion of patients that respond to PARPi. The authors hypothesized that increased DNA damage by olaparib will complement anti-tumor activity of immune checkpoint blocking antibody, durvalumab, among mCRPC patients.

This trial was a single arm pilot study with accrual of 25 patients with mCRPC and disease that was amenable to biopsy. Prior treatment with enzalutamide and/or abiraterone was required. Durvalumab was given at 1500 mg IV every 28 days + olaparib 300 mg tablets PO every 12 hours. The primary endpoint was progression-free survival (PFS), secondary objectives were safety and response rate measured by PSA and imaging, and exploratory objectives included mutational analysis of on-study biopsies, and chemokine/cytokine analysis.

In the first 17 patients, 94% were pretreated with enzalutamide, 65% with abiraterone, and 59% with both agents; 65% of patients were also previously received chemotherapy. The median age was 66 (range 45-79 years), median baseline PSA was 80 ng/mL [3.93-24 ng/mL]), and median Gleason score was 8. There were six patients with bone only disease and 11 patients with bone and soft tissue/visceral disease. The median number of durvalumab cycles was 7 (range 2-17). Grade 3 and 4 adverse events included anemia (24%), lymphopenia (12%), infection (12%), thrombocytopenia, leukopenia, neutropenia, nausea, vomiting, UTI, hypertension, hearing impairment, fatigue, syncope, oral mucositis, muscle weakness, and muscle cramps (6% each). Eight patients (47%) had PSA responses >50%, and six of these patients had mutations in the DNA damage repair pathways. Two patients (11%) had PSA responses >30% with no known mutations in DNA damage repair pathways. Four patients (22%) had a partial response, the median radiographic PFS was 16.1 months (95%CI 4.5-16.1), and the 12 month PFS was 51.5% (95%CI: 25.7-72.3%).

Dr. Karzai concluded that durvalumab potentially enhances PFS with olaparib in patients with mCRPC who have been treated with enzalutamide and/or abiraterone. Toxicities are manageable, but there are significant adverse events observed. Ultimately, additional studies are needed to elucidate possible synergistic mechanisms, such as the STING pathway, increased neoantigens, and immunogenic modulation. This clinical trial will be expanded to enroll up to an additional 65 patients. 

Clinical trial information: NCT02484404


Presented by: Fatima Karzai, National Cancer Institute at the National Institutes of Health, Bethesda, MD

Co-Authors: Ravi Amrit Madan, Helen Owens, Anna Couvillon, Amy Hankin, Monique Williams, Marijo Bilusic, Lisa M. Cordes, Jane B Trepel, Keith Killian, Paul S. Meltzer, James L. Gulley, Jung-min Lee, William L. Dahut

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA


References: 

1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.
2. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
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