PARP Inhibitors Have Made Significant Progress in BRCA1/2 Metastatic Breast Cancer, but Limitations Remain

Metastatic breast cancer has a poor prognosis, but emerging targeted therapies are providing some progress in the treatment of the disease, Filipa Lynce, MD, medical oncologist at Dana-Farber Cancer Institute and Harvard Medical School, explained during her session at the National Association of Managed Care Physicians Virtual Spring Managed Care Forum.

When first consulting with new patients, Lynce often provides a snapshot of the disease, making sure they understand that breast cancer is a very common disease, affecting 1 in 8 women in the United States. However, patients who are initially diagnosed with metastatic breast cancer only have a 5-year survival rate of 28%.

“Although we have a lot of survivors of breast cancer, still we are losing a lot of lives to breast cancer,” Lynce said.

Her session focused largely on BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors. Currently, there are only 2 PARP inhibitors approved in breast cancer: olaparib and talazoparib. Other PARP inhibitors that have been approved are only for use in ovarian cancer at this time.

The various PARP inhibitors available have different PARP trapping potency and different capacities for inhibition, and it is unclear whether those differences are clinically significant, she said. In order to determine that, there would need to be head-to-head comparisons of the PARP inhibitors, which has not happened yet and likely won’t happen, according to Lynce.

A table of toxicities highlighted the different toxicity profiles of the PARP inhibitors, during which Lynce reminded the audience that they are being used instead of chemotherapy.

“So even if you look at these and think, ‘There’s a lot of hematological malignancy,’ all studies have shown that the quality of life is far better with PARP inhibitors than chemotherapy, which is the alternative for most of these patients,” she said.

The adverse effects of PARP inhibitors are mainly hematological, with thrombocytopenia and anemia more prevalent in talazoparib than olaparib. The labels for these therapies also mention that there is the potential to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While these may be rare, PARP inhibitors are fairly new, and more long-term follow-up data are needed to understand how significant the risk is.

In addition, Lynce pointed out that these patients have metastatic breast cancer, and the development of MDS or AML down the road in an already deadly disease takes on different significance than if these drugs move to earlier use.

She highlighted a few studies evaluating the use of PARP inhibitors in metastatic breast cancer and BRCA1/2 carriers. First, the OlympiAD study showed an improvement in quality of life using olaparib compared with chemotherapy in patients who had received 1 to 2 prior lines of chemotherapy.¹ The median progression-free survival (PFS), which was the primary end point, was 2.8 months longer; however, the overall survival (OS) did not differ significantly between the groups.

The EMBRACA study had a similar study design evaluating talazoparib, and the primary end point was PFS again.² While there was an improvement in PFS vs chemotherapy, “we see that we still need to do better for these patients.” The median PFS for the PARP inhibitor was 8.6 months vs 5.6 months on chemotherapy. Again, OS did not differ significantly.

In TBCRC 048, olaparib was studied in patients with metastatic breast cancer who had germline or somatic mutations.³ All patients in the study received olaparib. Cohort 1 had germline mutations (no BRCA1/2 mutations) and cohort 2 had somatic mutations (including BRCA1/2). A total of 15 patients in cohort 2 had somatic BRCA1/2 mutations. The partial response (PR) in this cohort was 31%, and all confirmed PRs had BRCA1/2 mutations. The PR in cohort 1 was 33%. There were confirmed responses in somatic BRCA1/2 (objective response rate [ORR], 50%) and germline PALB2 (ORR, 82%). Although it was only a small number, none of the patients with ATM (n = 13) and CHEK2 (n = 4) mutations had a PR.

Studies are also now looking at whether PARP inhibitors can be combined with immuno-oncology (IO). MEDIOLA, a phase 1/2 open-label trial of olaparib and durvalumab, studied patients with ovarian, breast, small cell lung, and gastric cancers.⁴ Patients were treated with olaparib alone for 4 weeks and olaparib and durvalumab until disease progression. There were a total of 34 patients with breast cancer: 47% with the BRCA1 mutation and 53% with the BRCA2 mutation. The ORR was 63.3%, and the median PFS was 8.2 months.

Lynce then did something that isn’t normally recommended: she compared the MEDIOLA results with the OlympiAD results. Although there are many caveats to comparing these trials, such as the different patient populations, the previous treatments, and the various agents, she did this to remind the audience that the ORR for OlympiAD was 59.9% and the PFS was 7.2 months.

“I think that all that we can say from these [results] is that the combination of a PARP inhibitor with IO, at least just based on this trial…does not strike us as a home run,” Lynce said.

However, she noted the benefit of IO is the durability of the response, which means it would be important to follow the patients of the MEDIOLA trial for a longer period of time.

In the TOPACIO/KEYNOTE-162 study,⁵ niraparib plus pembrolizumab was evaluated in 55 patients with triple-negative breast cancer (TNBC) who had 1 prior line of therapy. Unlike MEDIOLA, all patients started immediately on the combination treatment. The ORR for all patients with TNBC was 21%, and for just those patients with BRCA mutations, the ORR was 47%.

These trials show that progress is being made, but there are still limitations, and trials are still looking at moving PARP inhibitors beyond the metastatic setting.

“You see these drugs work, but we need to find a way to bring more durable responses to these patients,” Lynce said. “But definitely, PARP inhibitors have changed how we treat these patients.”

References

1. Robson M, Im S-A, 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

2. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905

3. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274-4282. doi:10.1200/JCO.20.02151

4. Domchek SM, Postel-Vinay S, Im S-A, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020;21(9):1155-1164. doi:10.1016/S1470-2045(20)30324-7

5. Vinayak S, Tolaney SM, Schwartzberg L, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5(8):1132-1140. doi:10.1001/jamaoncol.2019.1029