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MIAMI BEACH -- The evolution of biomarker testing and concurrent development of new therapeutic options have created precision medicine opportunities in metastatic triple-negative breast cancer (mTNBC), an Atlanta breast cancer specialist said here.

Whereas chemotherapy followed by more chemotherapy had been the standard of care for years, treatment options for first line and beyond include immunotherapy, targeted therapies, and antibody drug conjugates (ADCs). Breast cancer specialists have greater flexibility to match patients to the most appropriate treatment as determined by biomarker assessment, said Kevin Kalinsky, MD, of Emory University and the Winship Cancer Institute, at the Miami Breast Cancer Conference.

"We have new agents for patients with mTNBC, but how do we think about sequencing these agents?" Kalinsky said at the beginning of his presentation. "It's critical to do PD-L1 testing for patients with newly metastatic [disease]. If they are positive, then I would propose it would be appropriate for them to receive chemotherapy plus checkpoint inhibition, with the checkpoint inhibition dependent on how PD-L1 positivity was defined."

"There are other indications for giving immunotherapy, such as high tumor mutational burden or MSI [microsatellite instability]-high, and pembrolizumab [Keytruda] has a single-agent indication. For patients with BRCA mutations, there are options that include platinum chemotherapy or a PARP inhibitor," he stated.

Patients who have PD-L1-negative/BRCA wild-type tumors should receive early consideration for genomic testing and enrollment in clinical trials, as no therapeutic approaches are approved for that indication, Kalinsky added.

Emergence of Immunotherapy

Immunotherapy initially found a niche in mTNBC by way of the IMpassion130 trial of nab-paclitaxel (Abraxane) plus atezolizumab (Tecentriq) or placebo as first-line therapy. The addition of the PD-L1 inhibitor led to a clinically meaningful 33% reduction in the survival hazard and a median overall survival (OS) of 25.4 months versus 17.9 months in the PD-L1+ subgroup in the .

On the basis of the IMpassion130 data, the FDA granted accelerated approval for the atezolizumab combination in patients with PD-L1 expression ≥1% by an FDA-approved test. Celebration of the win was short lived as the follow-up IMpassion131 trial failed to show an improvement in progression-free survival (PFS) with atezolizumab plus paclitaxel in patients with newly diagnosed PD-L1+ mTNBC. Genentech subsequently withdrew the accelerated approval.

What went wrong? Kalinsky suggested one possible explanation: "Patients who received paclitaxel alone did quite well. They had a median OS of 20 months, so there was a difference in the control arm in this particular study."

Other possible explanations related to variability in PD-L1 expression by biopsy site, by primary versus metastatic tumor tissue, and by intrinsic molecular subtype of the tumor, he noted.

Immunotherapy regained footing in mTNBC with the KEYNOTE-355 trial, which showed statistically significant improvement in PFS and OS in PD-L1+ mTNBC with pembrolizumab plus investigator's choice of chemotherapy. The most recent analysis showed consistency of the outcome whether PD-L1+ was defined as ≥10% or ≥1%. The FDA approved the combination on the basis of the results.

PARP Inhibitors

For patients with PD-L1+ tumors and germline BRCA mutations, two different PARP inhibitors offer viable options as initial therapy, although no trials have compared the two strategies (anti-PD-1/L1 vs PARP inhibition), said Kalinsky. In the PD-L1-negative/BRCA+ setting, PARP inhibitors offer an alternative to chemotherapy, although either option is acceptable.

Olaparib (Lynparza) received FDA approval on the basis of the phase III OlympiAD trial of patients with metastatic breast cancer associated with BRCA1/2 mutations. Single-agent olaparib led to a median PFS of 7.0 months versus 4.8 months for chemotherapy.

Talazoparib (Talzenna) received a breast cancer indication on the basis of the EMBRACA trial, which showed a median PFS of 8.6 months with talazoparib versus 5.6 months with chemotherapy for locally advanced/metastatic breast cancer associated with a BRCA mutation. Continued follow-up in the trial did not show an OS benefit with the PARP inhibitor.

The phase III BROCADE 3 trial also showed a modest improvement in median PFS with veliparib in combination with a chemotherapy doublet (14.5 vs 12.6 months with chemotherapy alone, P=0.0016). Responses proved durable in many instances, as a third of patients randomized to veliparib remained progression-free after 36 months of follow-up. Notably, a small subgroup of patients with TNBC and BRCA mutations had a median OS of 36 months.

For patients who have PD-1/L1+ tumors and BRCA mutations, Kalinsky said he would begin treatment with a PD-1/L1 inhibitor and chemotherapy and reserve a PARP inhibitor for later use.

Several ongoing trials are evaluating PD-1/L1 inhibitors in combination with PARP inhibitors.

"There is certainly a preclinical rationale about the potential synergistic effects of giving these two together," said Kalinsky. "But what we are really awaiting is an answer to the question of whether there's a role for giving a PARP inhibitor plus immunotherapy, not so much to improve the response rate, but the durability of responses."

ADCs Impress

Most recently, the ADC sacituzumab govitecan (Trodelvy) has entered the conversation about therapeutic options for mTNBC. The phase III ASCENT trial evaluated the ADC in mTNBC that had progressed following two or more prior systemic regimens. The primary analysis showed a median PFS of 5.6 months with the ADC and 1.7 months for physician's choice of chemotherapy. Median OS almost doubled, from 6.7 months with chemotherapy to 12.1 months with sacituzumab govitecan.

The ADC, which targets the cell-surface antigen Trop-2, received accelerated FDA approval on the basis of a nonrandomized trial, followed by conversion to full FDA approval in 2021. Kalinsky called sacituzumab govitecan the ideal choice as third-line therapy for mTNBC.

Still other potential options for mTNBC have reached the therapeutic horizon, including the Trop-2-targeted ADC datopotamab deruxtecan and the HER2-targeted ADC trastuzumab deruxtecan (T-DXd, Enhertu).

"This time next year, I suspect we will be talking about trastuzumab deruxtecan and its potential role in patients with HER2-low breast cancer, which includes our patients with HER2-1+, HER2-2+, and unamplified tumors," said Kalinsky. "We have already seen a announcing there's an improvement in PFS and OS for these patients, and we are eagerly awaiting to see the data at an upcoming congress."

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