Traina Talks TNBC Treatment Evolution

Tiffany A. Traina, MD

Data from the phase III EMBRACA trial showed the superiority in progression-free survival (PFS) with the PARP inhibitor talazoparib in patients with germline BRCA1/2-mutant metastatic HER2-negative breast cancer, including patients with triple-negative disease (TNBC).

At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib compared with 5.6 months with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). The objective response rate was 62.6% versus 27.2%, respectively.

OncLive: What advances have we seen in TNBC?

What is the prevalence of BRCA mutations in TNBC? How have PARP inhibitors affected this population of patients?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Tiffany A. Traina, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the potential for PARP inhibitors, as well as immunotherapy and antibody-drug conjugates, for the treatment of patients with TNBC.Traina: There are 3 advances in TNBC I highlighted from the 2017 San Antonio Breast Cancer Symposium. The first are the data on the PARP inhibitor talazoparib in patients with metastatic disease and germline BRCA1/2 mutations. The second is the interest in immuno-oncology agents and checkpoint inhibitors. The third are the developments in antibody-drug conjugates and the encouraging results of sacituzumab govitecan (IMMU-132). This is the antibody-drug conjugate against Trop-2 that is conjugated to a metabolite of irinotecan.The prevalence of germline BRCA mutations is difficult to fully understand because physicians are unclear what the ultimate denominator is. The data presented at the 2017 San Antonio Breast Cancer Symposium showed that there are patients who should undergo clinical genetic testing so they can be aware of their germline BRCA status.

The data prior to the conference was related to the FDA approval of the PARP inhibitor olaparib in women with germline BRCA-mutated metastatic breast cancer. Data from the OlympiAD study revealed single-agent olaparib oral therapy was superior to physicians' choice of chemotherapy. That arm included capecitabine, eribulin, or vinorelbine. Olaparib had about a 40% improvement in median PFS for women with BRCA-mutated metastatic breast cancer. The safety profile was very tolerable relative to cytotoxic chemotherapy.

Will these data encourage the development of more PARP inhibitors in the space?

Where do you see immunotherapy fitting into the TNBC treatment paradigm?

At that meeting, we also saw the data from EMBRACA, a randomized phase III trial of the oral PARP inhibitor talazoparib. While the study populations were slightly different, the hazard ratios were quite comparable in terms of the prevalence of estrogen receptor—positive disease versus TNBC and the portion of patients treated in the first-line versus later line setting. In terms of toxicity, we saw a bit more hematologic toxicity with olaparib compared with chemotherapy. There is certainly the opportunity to explore other PARP inhibitors, but we need to understand which patients have germline mutations, as they are the likely candidates for this treatment. We also have trials in development that are looking at the role of PARP inhibitors in non-BRCA germline mutations and BRCA somatic mutations. We need to remind ourselves that these clinical trials underwent central testing; there were specific germline mutations that counted as pathogenic mutations. There is activity with PD-L1 inhibitors. Prior to the 2017 San Antonio Breast Cancer Symposium, we saw a small signal; several studies reported approximately a 20% to 25% response rate in the first-line setting. It seems that single-agent checkpoint inhibitors have greater activity in the frontline setting. We are most excited by the tail of the curve, which shows that there are some select patients who have durable responses. We would like to think there is an ideal biomarker to select those patients, but I haven't seen reports of that in trials to date. In terms of PD-L1 status, we often don't see dramatic differences in response.

How have antibody-drug conjugates impacted the landscape?

What does the future hold for TNBC?

The next question is whether these agents should be given with chemotherapy or with radiation therapy as opposed to monotherapy. The trial presented at the meeting by Sara M. Tolaney, MD, showed a tolerable safety profile with the combination of eribulin with pembrolizumab (Keytruda). It's a single-arm phase II trial, so it’s difficult to tease out what the incremental addition pembrolizumab offered. Nonetheless, it’s encouraging to see responses in both frontline and later-line settings in patients with metastatic TNBC. There are also many studies looking at partnering checkpoint inhibitors with taxane-based chemotherapy and nab- paclitaxel (Abraxane).Sacituzumab govitecan targets Trop-2, a highly expressed cell-surface glycoprotein found in TNBC. The use of this agent was examined in a phase II study presented at the 2017 San Antonio Breast Cancer Symposium. The trial was of particular interest to physicians because the agent showed significant response rates and longer median PFS than was expected from historical controls. These patients had already received taxane-based chemotherapy, anthracyclines, and prior platinum-based chemotherapy. Additionally, approximately 20% of patients received checkpoint inhibitors. The phase III randomized ASCENT study is a global trial that is comparing the use of sacituzumab govitecan with physicians’ choice of therapy. We're eagerly awaiting the results of that trial. The future is more encouraging than ever before. We are recognizing that TNBC is made up of multiple subtypes of breast cancer with different drivers. Now that we're aware of these drivers, the checkpoint interface, potential targets like Trop-2, BRCA germline status, and the androgen receptor, we’re able to develop effective therapies. There are great reasons to be excited about the future of TNBC.

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.