Durvalumab/Olaparib Combo Is Active in BRCA-Mutated Metastatic Breast Cancer

The combination of olaparib and durvalumab in patients with HER2-negative metastatic breast cancer with germline BRCA mutations is well tolerated and has promising activity, especially in earlier settings.

Susan M. Domchek, MD

The combination of olaparib (Lynparza) and durvalumab (Imfinzi) in patients with HER2-negative metastatic breast cancer with germline BRCA mutations is well tolerated and has promising activity, especially in earlier settings, according to an interim analysis from the open-label phase II MEDIOLA trial.1

Findings from the ongoing study showed a disease control rate of 80% (24 of 30 patients; 90% CI, 64%-91%) at 12 weeks in the entire study population, which was the primary endpoint of the study. In addition, the overall response rate (ORR) was 63% (95% CI, 44%-80%) at 28 weeks, the median duration of response (DOR) was 9.2 months (range, 5.5-13.1), and the median progression-free survival (PFS) was 8.2 months (95% CI, 4.6-11.8) at 28 weeks. At 28 weeks, the disease control rate was 50% (90% CI, 34%-66%).

The median DOR compares favorably to the median of 6.4 months with olaparib monotherapy observed in the OlympiAD study in patients with BRCA-mutated metastatic breast cancer,2 which led to olaparib’s approval for this indication, according to data presented by Susan M. Domchek, MD, and colleagues at the 2018 San Antonio Breast Cancer Symposium. The median PFS in OlympiAD was 7.0 months.

With 34 patients enrolled and a data cutoff of June 30, 2018, efficacy could be evaluated in 30 patients. Overall survival data remain immature.

Response rates were greater when the olaparib/durvalumab combination was used earlier in the course of therapy. The median DOR in patients with 0 or 1 line of prior chemotherapy (n = 14) was 12.9 months, and in those with 2 prior lines of chemotherapy (n = 5), the median DOR was 5.5 months. The median PFS was 11.7 months (95% CI, 4.57-13.77) in patients treated with 0 or 1 prior line of chemotherapy and 6.5 months (95% CI, 0.99-8.25) in those treated with 2 lines.

“This is a relatively small study,” said Domchek, the Basser Professor in Oncology and director of the MacDonald Women’s Cancer Risk Evaluation Program at the University of Pennsylvania in Philadelphia. “We saw response rates in the same range as olaparib monotherapy, and the question is whether we’ll see a longer duration of response. There is some suggestion of that, particularly in patients who receive 0 to 1 lines of therapy, but one must be very careful of cross-trial comparisons, although there appears to potentially be some prolongation of both duration of response and PFS. We need a larger trial, which is planned to an expansion cohort in this patient population.”

MEDIOLA enrolled 34 patients with HER2-negative locally advanced or metastatic breast cancer and a histologically confirmed germline BRCA mutation in the breast cancer cohort. Patients received prior anthracycline and/or taxane therapy but prior PARP inhibitor or immunotherapy was not allowed. After a 4-week run in which patients received olaparib at 300 mg twice daily, they were treated with olaparib, 300 mg twice daily, and durvalumab, 1.5 g intravenously every 4 weeks. The combination was continued until progressive disease by RECIST 1.1 criteria.

“The idea is that if you can get a response with olaparib, it’s possible that durvalumab will lead to a longer duration of response because olaparib generates DNA damage, so that there may be some more antigens expressed and then the durvalumab will do almost auto-vaccination, producing a prolonged response,” Domchek said.

Tumor assessments were by CT or MRI performed at baseline, 4 weeks, and every 8 weeks thereafter.

Median patient age was 45.0 years (range, 29-66), and only 1 patient was male. Half of the patients had documented BRCA1 mutation, and the other 50% had a BRCA2 mutation. Hormone receptor status was positive in 43% and the other 57% had triple-negative breast cancer. Thirty percent received no prior chemotherapy, 37% received 1 line, and 33% received 2 lines. Some 43% had prior platinum therapy.

The median DOR of 80% at 12 weeks exceeded the prespecified target of 75%, “raising the possibility that the addition of durvalumab further enhances the upfront efficacy of olaparib monotherapy in germline BRCA-mutated patients,” the investigators declared in their poster presentation.

PD-L1 expression >25% in immune cells and tumor cells obtained at baseline and after olaparib monotherapy run-in predicted a response to treatment in 3 of 5 patients with paired biopsies. Two patients with PD-L1 expression <25% had progressive disease. The data also suggest that patients who had high or increased densities of T cells (CD3+) and cytotoxic T cells (CD8+) after 4 weeks of olaparib predicted clinical response.

The most common grade ≥3 adverse events (AEs) attributed to olaparib were anemia (12% and neutropenia (6%), and the most common grade ≥3 AE attributed to durvalumab was pancreatitis (6%).

References

  1. Domchek SM, Postel-Vinay S, Im S-A, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Presented at San Antonio Breast Cancer Symposium; December 5-7, 2018; San Antonio, TX. Abstract PD5-04.
  2. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi: 10.1056/NEJMoa1706450.

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