Neoadjuvant Niraparib Plus Dostarlimab Data Support Development of Non-Chemo Approaches in BRCA+, ER+ Breast Cancer

Erica L. Mayer, MD, MPH

The continued evaluation of targeted, non-chemotherapy approaches and immunotherapies in the neoadjuvant setting is of great importance for patients with breast cancer harboring germline BRCA1/2 mutations, according to Erica L. Mayer, MD, MPH, who added that new data showing pathologic complete responses (pCRs) and minimal residual disease with preoperative niraparib (Zejula) plus dostarlimab-gxly (Jemperli) support such efforts.

Findings from arm C of the phase 2 TBCRC 056 trial (NCT04584255), comprising patients with estrogen receptor (ER)–positive, HER2-negative, BRCA/PALB2-mutated breast cancer (n = 18), were presented at the 2024 San Antonio Breast Cancer Symposium (SABCS). Following treatment with neoadjuvant niraparib plus dostarlimab, the pCR rate (pCR) was 16.7% (90% CI, 4.7%-37.7%); the residual cancer burden (RCB)-0/I rate was 44.4%. Responses were observed in 11.1% of patients who received additional neoadjuvant therapy.

“We also saw that [the regimen] was able to modestly influence tumor-infiltrating lymphocytes [TILs], and baseline TIL [levels] were predictive of response at surgery,” said Mayer, the director of clinical research at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts. “[Based on these findings,] we are interested in further exploration of non-chemotherapy approaches for BRCA-associated breast cancer, as well as the use of immunotherapy for ER-positive disease.”

In an interview with OncLive^®, Mayer discussed the rationale for evaluating a targeted, non-chemotherapy neoadjuvant treatment approach for patients with breast cancer harboring germline BRCA1/2 or PALB2 mutations; early efficacy and safety results from the TBCRC 056 study; and the importance of large, prospective studies in this rare patient population.

OncLive: What is the rationale behind combining a PARP inhibitor with immunotherapy in the treatment of patients with early-stage breast cancer harboring germline BRCA1/2 mutations?

Mayer: PARP inhibitors are broadly used in the management of breast cancer for patients with germline BRCA1/2 gene mutations. Preclinical data suggest that there may be increased efficacy when you combine a PARP inhibitor with an immunotherapy approach. The idea is that exposure to the PARP inhibitor stimulates the cGAS-STING pathway, which leads to T-cell recruitment, and that ultimately may lead to enhanced immune effects. There's a strong rationale to combine these 2 [therapies]. Although the combination has been [evaluated] at in the metastatic setting, we think its greatest activity may be seen in the early-stage setting, which is a less immunosuppressed space.

What was the design and methodology of the TBCRC 056 trial?

TBCRC 056 is a prospective, phase 2 multicenter study run through the Translational Breast Cancer Research Consortium. The trial has 3 arms, 2 of which are designed for triple-negative breast cancer [TNBC]. Those arms are not yet ready for reporting.

At the 2024 SABCS, we reported on the ER-positive arm of the study. This is an exploratory arm designed to enroll 18 patients with ER-positive disease, defined as [an expression level of] 10% or more. Eligible patients also had stage I-III breast cancer with a tumor size of 1 cm or more, HER2-negative [disease], and a germline BRCA1/2 or PALB2 mutation. Treatment [comprised] 18 weeks of combination therapy using the PARP inhibitor, niraparib, and the PD-1 inhibitor, dostarlimab. Each cycle was 3 weeks, for 6 cycles total. Patients then could go on to surgical resection. If there wasn't enough response, they could cross over and receive additional systemic therapy before surgery. We also had mandatory tissue collection at baseline and cycle 2 day 1, which was 3 weeks into treatment, and at end of treatment.

What efficacy and safety results from arm C were presented at the meeting?

The primary objectives of the study, which were exploratory for arm C, included pCR [rate] and whether this combination therapy could recruit [basal-like (BL) and C2] stromal TILs into the tumor between baseline and 3 weeks. All 18 patients [treated on the study went] to surgery. In general, we found that, in this small exploratory cohort, 18 weeks of therapy with a PARP inhibitor and a PD-1 inhibitor [with] no chemotherapy led to a pCR rate of 16.7% and an RCB 0/1 rate of 44.4%, which means a near pCR.

When considering the second end point, TIL recruitment, 12 patients had paired samples between baseline and cycle 2. When we evaluated these patients, we saw a numerical increase in TILs of 11.9%. We also looked at whether TILs could predict response at surgery. Seventeen patients had evaluable baseline TILs. When we looked at TILs as a continuous variable, the number of baseline TILs did predict whether patients would have a pCR at the time of surgery.

The toxicities that were seen with the regimen were as expected for these types of therapies. The most common toxicities we saw were rash, LFT abnormalities, and diarrhea.

How does TBCRC 056 highlight the importance of large, prospective studies to address the treatment needs in rarer breast cancer subgroups?

TBCRC 056 is a study exclusively for patients with germline mutations. This is a fairly rare population of patients in our practice and when they are initially diagnosed, [they] may not actually know if they have a gene mutation. I'm very grateful to the collaborative efforts within the TBCRC to identify and recruit patients onto the study. We can only move forward for the subset of breast cancer by doing large studies, prospective studies that look at novel therapies and try to help improve outcomes for these patients. There are TNBC arms in TBCRC 056 and we look forward to sharing those results at a future congress.

Reference

Mayer EL, Graham N, Leon-Ferre RA, et al. TBCRC 056: a phase II study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the ER+/HER2- cohort. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract RF3-01.