NEW YORK – Metastatic breast cancer patients with BRCA1/2 mutations who were treated with the combination of AstraZeneca's PARP inhibitor olaparib (Lynparza) and its checkpoint inhibitor durvalumab (Imfinzi) had similar response and stable disease rates as patients receiving these drugs as single agents, researchers reported recently in Lancet Oncology.
Based on data from the AstraZeneca-sponsored Phase I/II MEDIOLA basket trial, the investigators led by University of Pennsylvania's Susan Domchek concluded that the olaparib-durvalumab regimen should be studied further in randomized trials, particularly in specific patient subsets, such as those with triple-negative breast cancer, those receiving the combination in earlier lines of therapy, and those with PD-L1-expressing tumors.
The MEDIOLA trial is exploring the activity of the olaparib-durvalumab combination across multiple solid tumor cohorts. Domchek and colleagues last week reported the efficacy and safety from one of the study cohorts involving metastatic breast cancer with germline BRCA1/2 mutations. Patients received twice daily olaparib tablets for the first four weeks and then a combination of olaparib twice daily and durvalumab intravenously every four weeks until their disease progressed or they couldn't tolerate the toxicities.
Out of 30 patients included in the response analysis, 24 patients, or 80 percent, saw their tumors shrink or had stable disease at 12 weeks. The median duration of response was 9.2 months.
Olaparib is already approved in the US for HER2-negative metastatic breast cancer patients with germline BRCA1/2 mutations after they've received chemotherapy. Durvalumab is not approved for breast cancer but in studies has shown promising activity in triple-negative breast cancer patients or those with PD-L1-positive tumors. Researchers have hypothesized that these two types of drugs may work well together to improve the immune system's ability to recognize and kill cancer cells.
BRCA1/2-mutant breast cancer cells already have hobbled DNA repair mechanisms, and PARP inhibitors work particularly well in patients with these mutations by causing overwhelming damage that cancer cells cannot repair, resulting in their destruction. Checkpoint inhibitors, meanwhile, unleash the immune system's ability to recognize and kill cancer cells. Since PARP inhibitors cause DNA damage, researchers expect these drugs may work synergistically with checkpoint inhibitors to charge up the immune system's ability to kill cancer cells.
In the TOPACIO trial, niraparib (GlaxoSmithKline's Zejula) was paired with pembrolizumab (Merck's Keytruda) and showed promising activity in advanced or metastatic TNBC patients, particularly those with BRCA1/2-mutated tumors. In 15 patients with BRCA1/2 mutations in their tumors, the objective response rate was 47 percent and the disease control rate was 80 percent.
At the American Association for Cancer Research's Virtual Annual Meeting earlier this year, researchers presented data showing that adding durvalumab to olaparib and standard-of-care neoadjuvant chemotherapy improved pathologic complete response in women with stage II/III HER2-negative breast cancer compared to chemotherapy alone. However, responses according to patients' BRCA1/2 mutation status wasn't available at the time of the presentation.
"Increasing evidence shows an interaction between olaparib-induced DNA damage and the immune system," Domchek and colleagues wrote in Lancet Oncology. "Preclinical data suggest that PARP inhibitors might elicit an antitumor immune response and provide the rationale for investigating olaparib in combination with durvalumab in germline BRCA1-mutated and BRCA2-mutated metastatic breast cancer."
However, because MEDIOLA is exploring the activity of the olaparib-durvalumab combination in single-arm cohorts, Domchek and colleagues couldn't draw definitive conclusions about the ability of the regimen to improve survival outcomes over single-agent treatment with these drugs. In the study, at a median follow up of 6.7 months, median progression-free survival was 8.2 months, and at a median follow-up of 19.8 months, median overall survival was 21.5 months. This was similar to the activity of durvalumab and olaparib in prior monotherapy trials, the researchers noted.
"This study was not randomized and was small with a heterogeneous population," Domchek acknowledged, but she noted encouraging signals in patients who received the olaparib-durvalumab combination in the early-line settings and in triple-negative breast cancer patients.
In the study, all breast cancer patients were HER2-negative, but researchers also looked at treatment outcomes based on whether they were hormone receptor-positive (i.e. estrogen or progesterone receptor-positive) or had triple-negative tumors. Domchek and colleagues also analyzed outcomes according to the line of therapy patients were on, as well as their chemotherapy status, PD-L1 status, tumor mutational burden, and PAM50 subtype.
In triple-negative breast cancer patients, median progression-free survival was only 4.9 months and median overall survival was 20.5 months. Among patients with hormone receptor-positive breast cancer, the median progression-free survival was 9.9 months and median overall survival was 22.4 months.
Domchek and colleagues suspect that the low median progression-free survival in the TNBC group may have been due to the fact that several patients experienced early disease progression. But the investigators still found it compelling that median overall survival was similar between the two groups, despite the fact that TNBC patients typically have much worse outcomes than hormone receptor-positive patients.
At data cut off, one TNBC and two estrogen receptor-positive breast cancer patients remained on the olaparib-durvalumab regimen. In particular, the TNBC patient was on therapy without progression for two-and-half years.
In this relatively small study, similar rates of TNBC and hormone receptor-positive breast cancer patients saw their tumors shrink on the olaparib-durvalumab regimen — 58.8 percent versus 69.2 percent, respectively. Domchek noted that prior randomized Phase III studies in BRCA1/2-mutated metastatic breast patients comparing single-agent PARP inhibitors against chemotherapy, such as OlympiaD and Embarca, had not demonstrated response differences based on hormone receptor status.
However, the median duration of response in MEDIOLA of 12.9 months in the triple-negative group versus 7.2 months for those with hormone receptor-positive disease, was "intriguing," Domchek said, "given the difficulty of treating [TNBC]."
When investigators looked at treatment outcomes based on patients' prior lines of therapy, outcomes were better in those who received the regimen as an earlier-line option. In patients who received the olaparib-durvalumab combination as a first- or second-line treatment, median overall survival was 23.4 months compared to 16.9 months for those who received the regimen as a third or later-line option.
"I would certainly like to see more data in the first-line setting to better understand any additional benefit of [adding] durvalumab to olaparib," Domchek said.
PD-L1 expression is a predictive biomarker of particular interest because these receptors on tumor and immune cells help cancer cells hide from the immune system. When researchers compared patients who had PD-L1 expression on tumor cells of 1 percent or more against those with expression levels below 1 percent, the objective response rate was 80 percent versus 52.9 percent. Median duration of response was 9.1 months versus 7.2 months, and median overall survival was 23.9 months versus 18.8 months in the PD-L1-positive and -negative groups, respectively.
The survival outcomes were similar when researchers looked at PD-L1 expression levels on patients' immune cells and CD8 expression levels, but these findings "need to be considered hypothesis generating," Domchek said.
In the Lancet Oncology paper, researchers flagged PD-L1 status, early versus late-line treatment, and hormone receptor status as three factors that should be studied further in larger cohorts to understand if they are predictive of benefit with olaparib-durvalumab in BRCA1/2-mutated, metastatic breast cancer patients.
Meanwhile, researchers didn't find any outcomes differences based on whether patients had BRCA1 mutations or BRCA2 mutations. PAM50 subtypes were available for 18 patients, but researchers found no correlation between intrinsic subtypes and outcomes on olaparib-durvalumab. Similarly, only 19 patients were evaluable for tumor mutational burden — five with medium TMB levels and 14 with low TMB — but researchers reported no association with treatment response.
The data on TMB in this MEDIOLA cohort "is insufficient to make any statement" about the predictive power of the biomarker, Domchek said. "However, the question in this situation may be the induction of immunogenicity from olaparib," she added. "We need more data to answer that question."