Abstract PD6-11: An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC)

Abstract

Background Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor, with first-in-class approval (400 mg capsules BID) for BRCA-mutated advanced ovarian cancer. Olaparib was recently found to be superior compared with chemotherapy in HER2-negative gBRCAm MBC in the Phase III OlympiAD trial. Olaparib induces DNA damage and genomic instability in gBRCAm tumors, which is hypothesized to result in enhanced immunogenicity. Here, we assess if a combination of olaparib and an anti-programmed cell death ligand-1 (PD-L1) agent, durvalumab, leads to enhanced antitumor activity in one of the four cohorts (NCT02734004). Methods Individuals with deleterious gBRCA1 or BRCA2 mutations and HER2-negative MBC were eligible. Patients with prior platinum therapy were allowed to enter if they had not experienced disease progression on platinum. No more than two prior lines of chemotherapy were allowed for metastatic disease, and patients with hormone receptor (HR) positive disease had to have at least one line of prior endocrine therapy. Concomitant use of endocrine therapy was not allowed. All patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease (PD) by RECIST 1.1 criteria. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoint was disease control rate (DCR) at 12 weeks, and safety and tolerability of the combination. The secondary endpoints included DCR at 28 weeks, objective response rate, duration of response, progression-free survival (PFS) and overall survival. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Olaparib monotherapy has previously demonstrated a median PFS (mPFS) of 6 months in this patient population, and addition of durvalumab was predicted to increase the mPFS to 7.5 months, corresponding to a target DCR of 75% at 12 weeks. This was achievable by enrolling 30 patients using a Bayesian predictive probability design. Results of the first 25 patients are presented. Results Median age was 46 years (range 29−66); 11 and 14 patients had BRCA1 and BRCA2 mutations, respectively; 13 patients had HR positive disease, and nine had previously received platinum therapy. Median number of prior chemotherapy lines was 1 (range 0-4). Grade 3 or higher adverse events (AEs) were anemia (8%), neutropenia (8%), hemolysis (4%), dyspnea (4%), pancreatitis (4%), fatigue (4%), lymphopenia (4%) and leukopenia (4%). There was one grade 5 AE (dyspnea), which was attributed to disease progression. Observed DCR at 12 weeks was 80%. Eight confirmed responses and five unconfirmed responses were seen. The updated results from primary and secondary endpoints, including DCR at 28 weeks, as well as biomarker and PK data, will be presented. Conclusions The combination of olaparib and durvalumab was well tolerated, with no apparent overlapping toxicities. The efficacy of the combination at an early time point reached the target DCR in gBRCAm HER2-negative MBC, and warrants further investigation. Citation Format: Domchek SM, Postel-Vinay S, Bang Y-J, Park YH, Alexandre J, Delord J-P, Italiano A, You B, Bastian S, Krebs M, Wang D, Waqar S, Angell H, Learoyd M, Chang S-C, Gresty C, Herbolsheimer P, Kaufman B. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-11.

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

“…A phase II trial of durvalumab in combination with olaparib for selected advanced solid cancers (MEDIOLA) showed that this combination is well tolerated with no significant overlapping toxicities (108)(109)(110)(111). Clinical response measured as disease control rate at 12 weeks was 29%, 80%, and 81% in patients with advanced SCLC, germline BRCA1/2-mutant HER2-normal breast cancer, and germline BRCA1/2-mutant platinum-sensitive ovarian cancer, respectively (109)(110)(111). This same combination was also assessed in patients with CRPC, and reported a 12-month PFS of 51% in a population unselected for DDR variants (112).…”

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…Recent clinical trials demonstrate that adding PARP inhibitors may enhance activity of immunotherapy in breast cancer [71,72]. Several recent pre-clinical studies suggest that PARP inhibition enhances immunogenicity in models of ovarian and breast cancer and that combining the two results in synergistic effects [73][74][75].…”

“…TOPACIO, a multicenter, open-label phase 1/2 study evaluated the PARP inhibitor niraparib plus pembrolizumab in metastatic TNBC and advanced ovarian cancer and during the dose-finding portion of the trial, none of the eight evaluable patients progressed: 4/8 had objective response and 4/8 had stable disease [71]. The MEDIOLA trial of olaparib plus durvalumab included a cohort of BRCA1/2 mutant metastatic TNBCs and showed an objective response rate of 52% [72]. Collectively, these pre-clinical and early phase clinical data suggest that targeting or enhancing HR defects may enhance tumor immunogenicity and potentially sensitize to immune checkpoint inhibitors.…”

Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

“…27 The combination of PARPi and immunotherapy is one novel approach currently being investigated (Table S1). 28 found that, although combined CTLA4 and PARP1 inhibition was synergistic, combining a PD-L1/PD1i with a PARP1i had no effect.…”