ASCO 2017: Combination of PDL-1 and PARP inhibition in an unselected population with metastatic castrate-resistant prostate cancer (mCRPC)

Chicago, IL ( Novel therapies in prostate cancer are rapidly developing. PARP inhibitors are a group of inhibitors of the enzyme poly ADP ribose polymerase (PARP), which in turn results in a cell’s inability to repair single-strand DNA breaks. In patients with mutations in DNA repair genes, such as a BRCA1, BRCA2 and PALB2, this second insult can lead to cell death. As >20% of prostate cancers have somatic DNA repair gene defects (DRDs), and clinical trials with PARP inhibitors have demonstrated response rates up to 88% in patients with DRDs,1 PARP inhibitors may have an important role in the management of prostate cancer.

Immune checkpoint inhibitors (ICI’s) are another class of medications that have gained a lot of interest. With efficacy established in multiple other malignancies, its role in prostate cancer is still being determined. By blocking the immune checkpoint cascade, these agents enable a patient’s own immune system to overcome cancer’s immune evasion mechanism. 

As PARP inhibition leads to more DNA strand breaks and cell death, there is likely greater increase in creation and exposure to tumor neoantigens – proteins which can be recognized as non-self by a patient’s immune system. As such, the authors of this clinical trial postulate that treatment with both an ICI and a PARP inhibitor would amplify response. They utilized olaparib (O), a PARP inhibitor, and durvalumab (D), an anti-PD-L1 antibody.

Study Design:
This is a single-arm pilot study with a goal accrual of 25 patients, all of whom have to have been previously treated by enzalutamide or abiraterone. Durvalumab is given at 1500 mg IV q28 days + Olaparib 300 mg orally q12h. Primary endpoint is progression-free survival (PFS). Secondary objectives included objective response rate (ORR), safety profile, and to correlate level of circulating tumor cells (CTCs) with clinical outcomes. 

So far, 19 patients have enrolled (median age 65 yr, median baseline PSA 79.67, mostly with Gleason score ≥ 8). All were treated with enzalutamide (35%), abiraterone (6%) or both (59%). Most were ECOG status 0-1. 63% had bony and visceral metastatic disease.

Grade 3/4 adverse events have included anemia (3/14, 21%), thrombocytopenia, lymphopenia, leukopenia, neutropenia, nausea, vomiting, hypertension, syncope, fatigue, UTI, and lung infection (1/14, 7% in the rest).  

Seven (of 16) patients (44%) on-study >2 months have had PSA declines > 50%. Six month and nine month PFS are 86.7% and 57.8%. Median PFS has not yet been reached.

Patients continued to be accrued. Paired tumor biopsy and blood samples are being collected to examine for biomarkers of response in the future.

Based on data so far, the combination or durvalumab and olaparib appears to be well tolerated. Early oncologic outcomes appear promising. 

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

Co-Author(s): Ravi Amrit Madan, Helen Owens, Amy Hankin, Anna Couvillon, Lisa M Cordes, Farhad Fakhrejahani, Nicole D. Houston, Jane B. Trepel, Clara Chen, Daniel C. Edelman, Paul S. Meltzer, Seth M. Steinberg, James L. Gulley, William L. Dahut, Jung-min Lee

Institution(s): National Cancer Institute, Bethesda, MD; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Institutes of Health, Bethesda, MD; Women's Malignancies Branch, National Cancer Institute, Bethesda, MD; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Center of Cancer Research, Bethesda, MD; Biostatistics and Data Management Section, CCR, National Cancer Institute, Bethesda, MD

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

1. Ramakrishnan Geethakumari P, Schiewer MJ, Knudsen KE, Kelly WK. PARP Inhibitors in Prostate Cancer. Curr Treat Options Oncol. 2017 Jun;18(6):37. doi: 10.1007/s11864-017-0480-2. Review.
2. Mateo J, Boysen G, Barbieri CE, Bryant HE, Castro E, Nelson PS, Olmos D, Pritchard CC, Rubin MA, de Bono JS. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol. 2017 Mar;71(3):417-425. doi: 10.1016/j.eururo.2016.08.037. Epub 2016 Aug 31. Review.