this part is very interesting:
“However, it has been shown that exposure to a PARP inhibitor will increase PD-L1 expression, and in preclinical models that does, in fact, lead to better response with these various therapies.” He concluded that the responses and the PFS achieved were compelling, especially with the limited toxicity.
Olaparib/Durvalumab Combo Shows Promise in mCRPC
onclive.com/conference-cove...
Wayne Kuznar
Published: Friday, Feb 09, 2018
The PARP inhibitor olaparib (Lynparza) appeared to complement the antitumor activity of the PD-L1 inhibitor durvalumab (Imfinzi) in unselected men with metastatic castrate-resistant prostate cancer (mCRPC), according to findings from a phase II study presented at the 2018 Genitourinary Cancers Symposium.
In the trial, 12 of 17 men with mCRPC treated with the combination had reductions in prostate-specific antigen (PSA) level, with 8 having PSA declines >50%,1 according to lead study investigator Fatima Karzai, MD, director of the Prostate Cancer Clinic, Cener for Cancer Research at the National Cancer Institute (NCI).
Men were chosen for the study regardless of their DNA damage repair mutational status. The median radiographic progression-free survival (PFS) was 16.1 months (95% CI, 4.5-16.1) in the overall cohort. Patients with mutations in DNA damage repair pathways (eg, BRCA2, BRCA1, ATM, CHK2) had superior median PFS compared with men without known mutations in DNA damage repair pathways (16.1 vs. 4.8 months, respectively).
About 20% of patients with advanced prostate cancer harbor DNA damage repair aberrations. In a landmark study that led to FDA breakthrough status, Mateo and colleagues2 showed that mCRPC patients with DNA damage repair aberrations had superior PFS with olaparib monotherapy compared with those without DNA damage in repair pathways.
In contrast, immune checkpoint inhibition has been a disappointment in the treatment of prostate cancer thus far, with no data to support its use except in patients whose tumors show high microsatellite instability, noted Karzai. “But emerging data suggest potential activity in combinations, as seen with results reported with enzalutamide (Xtandi) plus pembrolizumab (Keytruda) and with a DNA-based vaccine plus pembrolizumab.”
The data Karzai presented were from the first 17 patients of an ongoing study at the NCI of patients previously treated with enzalutamide and/or abiraterone acetate (Zytiga). They received olaparib at 300 mg orally every 12 hours plus durvalumab at 1500 mg intravenously every 28 days.
The primary objective was determination of efficacy as measured by PFS consistent with 70% PFS at 4 months. “This [endpoint] was chosen because with second-line treatment for CRPC, the PFS is expected to be approximately 3 to 4 months,” said Karzai.
Baseline characteristics were typical for patients with advanced prostate cancer. Some 94% had received treatment previously with enzalutamide, 65% with abiraterone, and 59% with both agents. Almost half (47%) had prior immunotherapy and 65% had prior chemotherapy. Eighty-two percent had an ECOG performance status of 1. The site of metastasis was bone only in 29% and bone/soft tissue/viscera in 70%.
At the time of mandatory pretreatment biopsy, only 3 patients were known to have mutations in DNA repair pathways. “PSA declines were seen in patients who had these aberrations in the DNA repair pathways and in some patients who did not,” said Karzai. “PSA declines were seen in patients with bone-only disease and in those who had bone, soft tissue, and visceral disease. There were several patients with deep declines.” The responses were durable.
In a comparison with radiographic PFS data from the clinical trial that led to the FDA breakthrough therapy designation for olaparib monotherapy in mCRPC, the median PFS in the biomarker-positive groups was 16.1 months with the combination in the NCI study versus 9.8 months with olaparib monotherapy, although Karzai admitted that such a comparison is not statistically fair. In the biomarker-negative groups, median PFS was 4.8 months in the NCI study and 2.7 months in the olaparib monotherapy study. “We are well aware that these results are very early on, and are likely to change with time,” she said.
Patients with a greater percentage of CD8 and CD4 T cells with activation markers appeared to have superior median PFS, she said.
Mechanisms by which the combination may enhance antitumor activity in patients without DNA damage repair include activation of STING pathway-dependent cytokine activity, Karzai indicated. Activation of the STING pathway correlates with interferon-β production and induction of antitumor T cells. In addition, olaparib may lead to immunogenic modulation of the tumor microenvironment in the form of an increase in the number of activated T cells. PARP inhibition may also cause more tumor-specific neoantigens.
Adverse events were as expected from previous PARP inhibitor trials, and included anemia (35%), lymphopenia (24%), nausea (18%), fatigue (18%), and diarrhea (18%). Immune-related adverse events included sudden-onset unilateral hearing impairment in 2 patients, optic neuritis in 1 patient, and 1 seronegative arthritis in 1 patient.
An expansion cohort of the study will enroll up to an additional 65 patients.
While the rationale for using checkpoint inhibition and PARP inhibitors is extremely strong in homologous recombination–deficient tumors, in patients who do not have underlying homologous repair deficiency, “it’s a little less clear how PARP inhibition will actually help. You can’t generate a BRCAness signature by treating a non-deficient tumor with a PARP inhibitor,” said invited discussant Bruce Montgomery, MD, clinical director of genitourinary medical oncology, Seattle Cancer Care Alliance. “However, it has been shown that exposure to a PARP inhibitor will increase PD-L1 expression, and in preclinical models that does, in fact, lead to better response with these various therapies.” He concluded that the responses and the PFS achieved were compelling, especially with the limited toxicity.
References
Karzai F, Amrit Madan R, Owens H, et al. A phase 2 study of olaparib and durvalumab in metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population. Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, Calif. Abstract 163.
Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697-1708.
<<< View more from the 2018 GU Cancer Symposium
Abiraterone/enzalutamide+PARP inhibitor better than abiraterone/enzalutamide alone for mCRPC, even without BRCA+
BRCA2 mutation and PARP inhibitor in the castration sensitive
