Novel Strategies Emerging to Tackle Heterogeneity of TNBC

Kari B. Wisinski, MD

Metastatic triple-negative breast cancer (TNBC) is a disease in which treatment was once heavily rooted in chemotherapy. Now, with the emergence of novel agents, clinicians are learning how to treat the heterogeneity of the disease appropriately, explained Kari B. Wisinski, MD, in a presentation during the 2019 OncLive^® State of the Science Summit^™ on Breast Cancer.

At the meeting, Wisinski, an associate professor and medical oncologist at the University of Wisconsin Carbone Cancer Center, highlighted modern day approaches for treating patients with metastatic TNBC.

Despite the emergence of these novel therapies, chemotherapy does still play a role in treatment, said Wisinski. Given the number of chemotherapeutics on the market and the preclinical data that pointed to the benefit of platinum-based chemotherapy, investigators set out to determine whether platinum-based chemotherapy would be superior to taxane-based chemotherapy in the TNT trial.

Patients with TNBC or a known BRCA1/2 mutation were randomized to receive either carboplatin or docetaxel and the alternate upon progression. Although there was no difference in objective response rate (ORR) among the entire population, the ORR was approximately doubled in patients with a BRCA1/2 mutation who received carboplatin.

For the majority of patients, however, the schedule and toxicity should guide chemotherapy decisions for each individual, said Wisinski.

PARP Inhibitors

Although chemotherapy has remained a cornerstone of treatment for patients with metastatic disease, PARP inhibitors have proven to be of immense value for select patients with disease progression. The first phase III study to demonstrate the efficacy of PARP inhibitors was the OlympiAD trial, which randomized patients who had progressed on ≤2 prior lines of chemotherapy 2:1 to receive either 300 mg of olaparib (Lynparza) or physician’s choice of chemotherapy.

The population was equally representative of hormone receptor (HR)—positive and triple-negative histologies; the majority of patients had received prior chemotherapy. However, only approximately 30% of patients had received a prior platinum-based agent.

Progression-free survival (PFS) served as the primary endpoint of the study and was 7.0 months with olaparib versus 4.2 months with chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P = .0009).¹ The benefit was magnified when the analysis was broken down by subtype, illustrating a 57% reduction in the risk of progression or death in TNBC and an 18% reduction in those with HR-positive disease.

Although there was no benefit in overall survival (OS) at either the interim analysis or at the time of final analysis (HR, 0.90; 95% CI, 0.66-1.23; P = .513), Wisinski noted that the study was not powered to analyze OS.

In terms of safety, the rate of grade ≥3 adverse events in the olaparib group was 36.6% versus 50.5% in the chemotherapy group. Furthermore, the rate of treatment discontinuation due to toxicities was 4.9% with olaparib versus 7.7% with chemotherapy. Quality of life was also better with olaparib than it was with chemotherapy, added Wisinski.

Subsequently, the phase III EMBRACA trial randomized a similar patient population 2:1 to a more potent PARP inhibitor, talazoparib (Talzenna), versus physician’s choice of chemotherapy.

“Not only does [talazoparib] inhibit PARP-1 and PARP-2, but it also traps PARP on single-stranded DNA breaks, and, therefore, may have more durable inhibition,” explained Wisinski.

In EMBRACA, the overall population was less representative of TNBC patients than those included in OlympiAD, with 45.3% of patients with TNBC in the talazoparib arm and 41.7% in the physician’s choice of chemotherapy arm.

Although the overall study was positive, with a median PFS of 8.6 months in the talazoparib arm versus 5.6 months in the chemotherapy arm (HR, 0.54; 95% CI, 0.41-0.71; P <.0001), there was no statistically significant improvement in OS observed.² Moreover, as in the OlympiAD trial, prior platinum exposure appeared to diminish the benefit of the PARP inhibitors.

Immunotherapy

Prior to the phase III IMpassion130 trial,³ the viability of immunotherapy in breast cancer seemed far-off following single-agent trials, explained Wisinski. However, by combining chemotherapy with immunotherapy in the frontline setting—in this case, nab-paclitaxel (Abraxane) with atezolizumab (Tecentriq)—investigators observed a 9.5-month improvement in OS versus nab-paclitaxel alone.

Subsequently, the combination became the first immunotherapy regimen to receive regulatory approval in breast cancer and is indicated as frontline therapy in treatment-naïve patients with ≥1% staining of PD-L1 on immune cells.

In the Pipeline

In terms of emerging treatment strategies, investigators believe androgen receptor (AR)—targeted therapy may prove fruitful for a subset of TNBC thought to be driven by the AR. These data are backed by small studies showing stabilization of disease, if not tumor shrinkage, said Wisinski.

Moreover, CDK4/6 inhibition, which has shown immense success in advanced HR-positive breast cancer, may also harbor activity in luminal-AR subsets. To test this theory, Wisinski and members of the Big Ten Cancer Research Consortium are opening a phase I/II trial of bicalutamide (Casodex), an antiandrogen, with ribociclib (Kisqali) in this patient population.

Another agent in the pipeline is sacituzumab govitecan.

“This is an antibody-drug conjugate against Trop-2, a linker, and then chemotherapy. The idea is that the antibody brings [the compound] to the tumor cells and then the chemotherapy is released at the site of the tumor cells,” Wisinski said.

In the pivotal phase II trial of sacituzumab govitecan, approximately one-third of patients achieved an objective response with the agent and the median duration of response was 9 months among the entire cohort, the population may have been fitter than the general population, as the median time to enrollment was 1.5 years.4

“This is a patient population who is already doing better than the average,” said Wisinski. “It’s important to think about when you consider the results of the study.”

Although the agent was granted an FDA breakthrough therapy designation last year, it still has not received regulatory approval.

Two additional classes of agents are PI3K-specific inhibitors and AKT inhibitors. While <10% of these cancers harbor a mutation in the PIK3CA gene, ≥50% will have loss of PTEN, which is the upstream regulator of the pathway.

Many of these agents have already shown activity as monotherapy, but one of them, gedatolisib, is thought to induce synergistic activity when used in combination with PARP inhibition in advanced or BRCA1/2-mutant TNBC. The dual PI3K and mTOR inhibitor is being explored in combination with the PARP inhibitor talazoparib, explained Wisinski.

In an ongoing phase I/II trial (NCT03911973), patients with TNBC or a germline BRCA mutation will receive a safety lead-in of daily talazoparib for 28 days followed by gedatolisib on days 1, 8, 15, and 22. The goal of the trial is to determine the recommended phase II dose of gedatolisib in combination with talazoparib and to assess the efficacy of this combination in patients with advanced HER2-negative breast cancer that is triple-negative or BRCA1/2-positive.

“Another direction we’re going in is exploring the combination of PARP inhibitors and checkpoint inhibitors,” said Wisinski. “Very early data from the MEDIOLA and TOPACIO trials showed some pretty significant responses that appeared to be more durable than what’s been seen with either agent alone.”

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(17):523-533. doi: 10.1056/NEJMoa1706450.
2. 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.
3. Schmid P, Adams S, Rugo HS, et al. IMpassion130: results from a global, randomised, double-blind, phase III study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2018;29(suppl 8; abstr LBA1_PR). doi: 10.1093/annonc/mdy424.008.
4. 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; December 5-9, 2017; San Antonio, Texas. Abstract GS1-07.