Fatima Karzai, MD
The combination of the poly ADP-ribose polymerase (PARP) inhibitor olaparib (Lynparza) and the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab (Imfinzi) produced positive preliminary results in men with metastatic, castration-resistant prostate cancer previously treated with abiraterone (Zytiga) and/or enzalutamide (Xtandi) in a small phase II trial presented at the 2018 Genitourinary Cancers Symposium.1
The trial is noteworthy because it combines a checkpoint inhibitor, which has up until now shown disappointing results in this setting, with a PARP inhibitor, which shows efficacy in prostate tumors that harbor mutations in DNA damage–repair pathways. Larger trials will be needed to demonstrate the usefulness of this combination in prostate cancer, and biomarkers will also be needed to identify patients likely to benefit.
“Durvalumab may enhance progression-free survival when combined with olaparib in patients who have been previously treated with enzalutamide or abiraterone. The toxicities of the combination were manageable. We plan to expand this study up to an additional 65 patients,” said lead author Fatima Karzai, MD, Director of the Prostate Cancer Clinic, Center for Cancer Research, at the National Cancer Institute (NCI) in Bethesda, Maryland.
“These data are not practice-changing, but they are intriguing. This study combines two of the hottest classes of drugs in prostate cancer, and the data, although early, are compelling,” commented ASCO Expert Sumanta K. Pal, MD, of City of Hope, Duarte, California.
“In these patients with metastatic, castration-resistant prostate cancer previously treated with enzalutamide and/or abiraterone, the combination of olaparib plus durvalumab reduced prostate-specific antigen (PSA) declines by more than 50% in about half the patients,” he continued. “We will need a biomarker-based approach to these drugs to tease out appropriate combinations. A logical next step could be a randomized trial comparing each of these classes of drug with the combination.”
About 23% of men with prostate cancer harbor DNA damage–-repair aberrations. In a previous study that led the U.S. Food and Drug Administration to grant the drug Breakthrough Therapy status,2 olaparib monotherapy achieved superior progression-free survival in men with metastatic, castration-resistant prostate cancer with DNA damage–repair mutations compared with those free of DNA damage in repair pathways. On the other hand, checkpoint inhibitors have been disappointing in prostate cancer trials, except for patients with tumors having high levels of microsatellite instability.
“Emerging data suggest potential activity in combinations [of these drug classes], as seen with enzalutamide plus pembrolizumab (Keytruda) and with a DNA-based vaccine plus pembrolizumab,” Dr. Karzai commented.
The current study included 17 men with metastatic, castration-resistant prostate cancer as part of an ongoing NCI study of patients previously treated with enzalutamide and/or abiraterone. Patients were treated with oral olaparib twice daily plus intravenous durvalumab every 28 days.
The primary endpoint was progression-free survival. Baseline characteristics were typical of patients with advanced prostate cancer. About 94% had received previous enzalutamide, 65% had previous abiraterone, and 59% had previous treatment with both agents. About half had prior immunotherapy, and about two-thirds had prior chemotherapy. Bone-only metastasis was present in 29% and bone, soft-tissue, or visceral metastasis, in 70%.
PSA declines were observed in 10 of 17 men treated with the combination. Eight patients had PSA declines > 50%. PSA declines were observed in patients regardless of whether they had mutations in the DNA repair pathway. (Three had DNA repair germline mutations, and two had somatic mutations.) PSA declines were also seen across all sites of metastasis, including bone-only, bone, soft-tissue, and visceral sites.
Median radiographic progression-free survival was 16.1 months for the group with mutations and 4.8 months in those without mutations. These rates compare favorably and are about 50% higher than those seen in the clinical trial that led to the Breakthrough Therapy designation for olaparib monotherapy.
“Expected progression-free survival in this group of patients is about 3 or 4 months,” she said. “The results are early and may change over time.”
Patients with a higher percentage of CD8 and CD4 cells with activation markers appear to have superior median progression-free survival, she noted.
Adverse events were similar to those reported previously with PARP inhibitors, including anemia (35%), lymphopenia (24%), nausea (18%), fatigue (18%), and diarrhea (18%). Adverse events considered to be immune-related included sudden-onset hearing loss in two patients, optic neuritis in one patient, and seronegative arthritis in one patient. ■
DISCLOSURE: Drs. Karzai and Pal reported no conflicts of interest.
1. Karzai F, Madan RA, Owens H, et al: A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer in an unselected population. 2018 Genitourinary Cancers Symposium. Abstract 163. Presented February 9, 2018.
2. Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373:1697-1708, 2015.
Robert Bruce Montgomery, MD
Formal discussant of this trial, Robert Bruce Montgomery, MD, Clinical Director of Genitourinary Medical Oncology, Seattle Cancer Alliance, said, “The rationale for checkpoint inhibition and [poly ADP--ribose polymerase (PARP)] inhibitors is strong in patients...!-->!-->