Earlier Diagnosis and Treatment Are Next Steps in TNBC Paradigm

Hope Rugo, MD

There is an unprecedented array of therapeutic options for patients with triple-negative breast cancer (TNBC), with more approaches on the horizon.

However, in the face of these promising investigational therapies, perhaps the most important issue in TNBC is that the focus must turn to diagnosis and treatment earlier in the disease course, said Hope Rugo, MD, in a presentation during the 2019 Lynn Sage Breast Cancer Symposium.

“Moving treatment to the early-stage setting is critical, because we clearly acquire mutations with treatment,” said Rugo, director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “This results in less efficacy and we may lose out on some great drugs based on doing our studies in the late-line setting.”

The current TNBC therapeutic landscape for early-stage TNBC includes optimal neoadjuvant therapy.

“If we add platinum to a taxane/anthracycline-based regimen, we see higher pathologic complete response (pCR) rates overall, regardless of the study,” she said. “However, there is increased toxicity and some reduced delivery of taxane/anthracycline, so I only add platinum for patients who aren't responding well or as an anthracycline-sparing agent. I will typically start with paclitaxel following cycle 4 if needed.”

Because recent trials were not powered to assess event-free survival, we don’t yet know the impact on long-term outcomes of platinum-based chemotherapy combined with standard chemotherapy, Rugo said. “In general, the issue of platinum is going to become a much more acute decision-making issue in the near future as we get more trial results from BrighTNess and KEYNOTE-522.”

PARP inhibitors have also been gaining momentum in this space, with the approvals of both olaparib (Lynparza) and talazoparib (Talzenna). Olaparib is indicated for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Talazoparib is available for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.

In the registration trials for olaparib and talazoparib, OlympiAD and EMBRACA, respectively, Rugo said, “We’re seeing great responses in patients who don't have platinum-resistant germline BRCA-associated breast cancer regardless of estrogen receptor (ER) status, but these responses are not as durable as we would like.”

In OlympiAD, olaparib was compared with standard chemotherapy in previously treated patients with BRCA-positive, HER2-negative breast cancer. Results showed that the median progression-free survival (PFS) was 7.0 months with the PARP inhibitor and 4.2 months in the physician’s choice group (HR, 0.58; 95% CI, 0.43-0.80; P = .001).²

Earlier this year, final overall survival (OS) data from OlympiAD were published, showing no statistically significant improvement in OS with olaparib versus physician’s choice of chemotherapy at 19.3 months and 17.1 months, respectively (HR, 0.90; 95% CI, 0.66-1.23; P = 0.513).³

In the EMBRACA trial, talazoparib was compared with chemotherapy in patients with BRCA-positive advanced breast cancer. Findings showed that the median PFS was 8.6 months in the talazoparib group compared with 5.6 months in the physician’s choice group.⁴ Mature OS data is not yet available, Rugo said.

“So, one question is whether or not carboplatin would be just as good as giving a PARP inhibitor, especially since most people tolerate them very well compared with platinum.”

Next steps for PARP inhibitors in breast cancer include examining them in both the neoadjuvant and adjuvant settings, in patients with other germline mutations with defects in DNA repair, and in those with somatic mutations, Rugo said. Combination therapies are also being explored, as is the question of whether maintenance therapy with PARP inhibitors may be as effective but less toxic than conventional chemotherapy.

Secondly, antibody-drug conjugates (ADCs) offer the hope of sensitive discrimination between cancer cells and healthy cells. ADCs combine highly selective monoclonal antibodies for a tumor-associated antigen with minimal expression on healthy cells, with a potent cytotoxic agent that can target cell death with internalization and release into the tumor cell—as well as a stable linker, she said.

Only one ADC is currently approved for breast cancer, which is trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive disease. However, several ADCs are currently in development for TNBC, Rugo said. For example, sacituzumab govitecan is a novel Trop-2 directed ADC.

“Trop-2 seems to be expressed on many different kinds of cancers, but we hadn’t really considered it to be a target previously,” she said. “The toxin is SN-38, the active metabolite of irinotecan, so it should be great for breast cancer.”

Updated results from a phase I/II trial of sacituzumab govitecan were published earlier this year, which demonstrated an overall response rate of 33.3% (95% CI, 24.6-43.1), and the median duration of response was 7.7 months (95% CI, 4.9-10.8).⁵

“These results were very good and there were no life-threatening toxicities,” Rugo said, noting that larger trials are also underway.

Other ADCs in development include ladiratuzumab vedotin, which targets the LIV-1 zinc transporter, as well as a microtubule-disrupting agent. U3-1402 is a novel anti-HER3 ADC currently being developed.

“HER3 is overexpressed in a lot of ER-positive breast cancers and a modest number of TNBCs, so we'll be seeing more trials with this ADC in the future,” Rugo said. “U3-1402 is quite intriguing and has the potential to be efficacious across different subsets of breast cancer.”

References

1. Rugo H. New Options for Triple Negative Cancer. Presented at: Lynn Sage Breast Cancer Symposium; October 3-6, 2019; Chicago, Illinois.
2. Robson ME, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. 2017;377:523-33. N Engl J Med. doi: 10.1056/NEJMoa1706450.
3. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558-566. doi: 10.1093/annonc/mdz012.
4. Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.
5. Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. Presented at: 2017 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 5-9, 2017. Presentation GS1-07.

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