“Triple-negative breast cancer has multiple different subtypes, and there are targeted therapies that can be used based on the biomarkers that we identify for each patient,” Kari B. Wisinski, MD, noted in a review of recently approved and emerging therapies at the 2020 Lynn Sage Breast Cancer Symposium, sponsored by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.1
Emerging therapies include targeting the PI3K pathway, in particular with the AKT inhibitors and taxane chemotherapy, she said, and targeting the androgen receptor, either with a single agent or in combinations, including the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. PARP (poly [ADP-ribose] polymerase) inhibitors might also be used in combination with PD-1/PD-L1 inhibitors, stated Dr. Wisinski, Associate Professor and Head of Solid Tumor Oncology at the University of Wisconsin Carbone Cancer Center, Madison.
Driven by Poor Prognosis
“Historically, we relied on chemotherapy to treat this disease,” Dr. Wisinski noted. However, she added, the “poor prognosis with a median overall survival of only 12 to 14 months” and the likelihood of triple-negative breast cancer to involve the visceral organs (including the brain, lungs, and liver) have driven the search for more effective systemic therapies.
Recently approved systemic therapies for metastatic triple-negative breast cancer include the PD-1/PD-L1 inhibitors atezolizumab, as a result of the IMpassion130 study, and pembrolizumab, as a result of the KEYNOTE-355 study. Combined with chemotherapy, these agents improved progression-free survival in PD-L1–positive, first-line, triple-negative breast cancer, and “the overall survival was also meaningfully improved in the exploratory analysis with atezolizumab,” Dr. Wisinski reported. Data on overall survival with pembrolizumab are not yet mature.
PD-L1 Testing Challenges
“The biggest challenge in my mind is PD-L1 testing and whether this is a strong biomarker for response to this treatment. If it is, the questions are which antibody should be used and which cutoff for positivity should be used to help decide which patients receive this combination therapy,” Dr. Wisinski asked. “Is that truly our best biomarker, or does it have to be PD-L1–positive as well as another biomarker to identify which patients are not only benefiting, but which ones have a durable disease benefit?”
In response to a question from a virtual symposium participant about the best way to test for PD-L1, Dr. Wisinksi responded: “It is a critical question that we still haven’t figured out in breast cancer and probably across tumor types.” Asked about the value of multiple and repeated molecular testing, Dr. Wisinski said that, for triple-negative breast cancer, “I am looking for anything that might potentially be a target early.”
“The PARP inhibitors have been shown to be of benefit in germline BRCA mutation carriers in terms of progression-free survival compared with standard nontaxane, nonanthracycline chemotherapies. To date, these studies have not shown an overall survival benefit, although there is a potential trend in first-line therapy.”
In the OlympiAD study, median progression-free survival was 7 months for patients who received olaparib vs 4.2 months for patients who did not.2 There was no difference in median overall survival, although “there was a trend in patients with no prior chemotherapy for metastatic disease to have an improved median overall survival from 14.7 months to 22.6 months,” Dr. Wisinski said.
The “highly potent” PARP inhibitor talazoparib improved progression-free survival to 8.6 months, compared with 5.6 months with chemotherapy in the EMBRACA trial,3 with just over 40% of the patients having triple-negative breast cancer. Median overall survival, however, did not differ between these two groups, Dr. Wisinski reported.
“Current studies are focusing on where PARP inhibitors fit into the treatment of carriers of nongermline BRCA mutations, what potential combinations may improve progression-free as well as overall survival, and how do we better understand the pathways of resistance to PARP inhibitors.”
Accelerated U.S. Food and Drug Administration approval was granted this year for sacituzumab govitecan in the previously treated triple-negative breast cancer setting. This novel antibody-drug conjugate targets Trop-2, which is an antigen on many solid tumors, including triple-negative breast cancer, explained Dr. Wisinski. “There is a linker to an SN-38 payload, which is a derivative of the parental compound, irinotecan, and is more potent.”
In a single-arm phase II study among women treated for triple-negative breast cancer who had two or more prior chemotherapies in the metastatic setting, the objective response rate, the primary endpoint, was “reported at 31% to 34%, depending on the investigator interpreting the scans,”4 Dr. Wisinski noted. “Complete responses were observed in a few patients, and it is important to note that the responses were durable, on average 7 to 9.5 months,” she added.
“One of the interesting findings is that the median time from metastatic disease to entry in this study was 1.5 years, which is more than the average survival for triple-negative breast cancer. The majority of patients were beyond the third or fourth line of treatment, and multiple different chemotherapy agents had been previously administered.”
The ASCENT study, a randomized, phase III trial comparing sacituzumab govitecan with physicians’ choice chemotherapy, has yielded encouraging findings, she added, and full results are awaited.
The PI3K/AKT Pathway
A total of 80% of triple-negative breast cancers “fall within the basal-like cluster on PAM-50 assay,” Dr. Wisinksi said, but there are many subtypes within the basal and nonbasal-like classes. “Each of these subtypes reflects different prognoses, chemotherapy responses, as well as different molecular targets, which can individualize the treatment for that specific subtype of triple-negative breast cancer.”
The LOTUS study, a randomized phase II trial evaluating paclitaxel alone or in combination with the AKT inhibitor ipatasertib, “demonstrated encouraging results,” Dr, Wisinski reported. “Progression-free survival was improved in the intention-to-treat cohort, from 4.9 to 6.2 months,” and in “patients with a PIK3 kinase alteration, from 4.9 months to 9 months. In addition, there were encouraging overall survival results, with an improvement of 16.9 months to 25.8 months in the intention-to-treat population and also a trend toward benefit in the biomarker cohorts.5 This is now being studied in an ongoing phase III study,” Dr. Wisinski said.
“One of the other interesting future directions for triple-negative breast cancer is the combination of PARP inhibitors with checkpoint inhibitors.”— Kari B. Wisinski, MD
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“The role of this pathway is further supported by the PAKT2 study.6 This was a randomized phase II study in first-line triple-negative breast cancer looking at another AKT inhibitor, capivasertib, in combination with paclitaxel or paclitaxel alone,” Dr. Wisinski stated. “Progression-free survival was improved in the intention-to-treat cohort but also in the PI3 kinase–altered cohort, with an improvement from 3.7 months to 9.3 months. A benefit in overall survival, again, appeared in the intention-to-treat cohort (12.6 months to 19.1 months). These results will be pursued in a phase III study.”
“One of the other interesting future directions for triple-negative breast cancer is the combination of PARP inhibitors with checkpoint inhibitors. This approach is based on preclinical studies showing that PARP upregulates PD-L1 expression in breast cancer cell lines and animal models and that the combination increased therapeutic efficacy in vivo,” Dr. Wisinski said.
“This combination has been evaluated in two studies,” she added. In the phase II TOPACIO study, among 47 evaluable patients with metastatic triple-negative breast cancer treated with niraparib and pembrolizumab, the objective response rate was 21%,”7 she reported. Five patients had complete responses, and another five had partial responses. Among the 15 patients “who had a tumor BRCA mutation, whether somatic or germline, 47% had a response,” Dr. Wisinski noted.
The MEDIOLA study8 included 34 patients with germline BRCA1/2 mutations and HER2-negative metastatic breast cancer, 57 % with triple-negative disease. All received olaparib with durvalumab. “Of 30 evaluable patients, 80% met the primary endpoint of disease control at 12 weeks,” stated Dr. Wisinski.
“Multiple other studies evaluating the combinations of PARP inhibitors and immunotherapies are ongoing,” she added.
Androgen Receptor Pathway
“Another interesting pathway is the androgen receptor pathway,” Dr. Wisinksi said.
A phase II study of enzalutamide in patients with androgen receptor–positive triple-negative breast cancer found a clinical benefit rate of 33% among patients with an androgen receptor positivity of 10% or higher.9 “There were a few cases of partial or complete responses,” but improvement in progression-free survival “remained modest,” according to Dr. Wisinski.
“Therefore, experts have been exploring other ways to target androgen receptor–positive triple-negative breast cancer.” A phase II study of the androgen receptor inhibitor bicalutamide with the CDK4/6 inhibitor palbociclib in 33 women with androgen receptor–positive, estrogen receptor–negative metastatic breast cancer found that “palbociclib as well as bicalutamide had activity.”10
“This study met its primary endpoint, with one-third of patients progression-free at 6 months. Although it does potentially appear that those patients with higher androgen receptor expression had more of a benefit, the numbers are quite small to make a definitive conclusion,” Dr. Wisinski continued. “This really highlights that we still don’t have the optimum biomarker for what is androgen-sensitive disease.”
We have designed a study evaluating ribociclib with bicalutamide in women with triple-negative breast cancer with androgen receptor positivity of 10% or higher, Dr. Wisinski announced. “This study includes a lead-in with bicalutamide for 2 weeks, in which circulating tumor cells will be collected and evaluated for androgen receptor signaling and localization to try to determine a better predictor of who benefits from this combination therapy.”
Preclinical data have shown that the novel combination of PARP inhibition with PI3 kinase inhibition “improves tumor response in both germline BRCA as well as wild-type triple-negative breast cancer cell models,” Dr. Wisinski reported. “This has led to the study being run by the BIG 10 Cancer Research Consortium to evaluate talazoparib in combination with gedatolisib, a dual PI3K mTOR inhibitor. This study will be evaluating patients with advanced triple-negative breast cancer as well as those with a germline BRCA mutation.” Dr. Wisinski serves as one of the principal investigators.
Based on the study findings and emerging data, Dr. Wisinski listed several approaches to consider in the treatment of triple-negative breast cancer.
“For the patient with first-line metastatic triple-negative breast cancer, I would consider PD-L1 tumor testing. If the patient tests positive for PD-L1, I would consider atezolizumab or pembrolizumab with chemotherapy. If the patient tests negative for PD-L1 and has a germline BRCA mutation, I would consider olaparib or talazoparib.”
“It is always reasonable to consider trials for patients in the first-line setting and beyond, to try to advance treatment in the future. In addition, one could consider other chemotherapy agents, PARP inhibitors if the patient has a germline BRCA mutation, or sacituzumab govitecan in the setting of two prior lines of chemotherapy.”
“Of note, triple-negative breast cancer has multiple different subtypes, and targeted therapies can be used based on the biomarkers identified for each patient.” There are multiple emerging targeted therapies, including PARP inhibitors for other DNA damage repair genes in germline or somatic BRCA1/2 mutations.”
“Targeting the PI3 kinase pathway, in particular with AKT inhibitors and taxane chemotherapy, is another option. Also targeting the androgen receptor, either with a single agent or in combinations (including CDK4/6 inhibitors), can be considered.
DISCLOSURE: Dr. Wisinski has served as a consultant or advisor to Genomic Health; has received research funding from Pizer; has received institutional research funding from AstraZeneca, Lilly, Novartis, and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Genomic Health.
1. Wisinski KB: Management of metastatic triple negative breast cancer. 2020 Lynn Sage Breast Cancer Symposium. Presented September 12, 2020.
2. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.
3. Litton JK, Rugo HS, Ettl J, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753-763, 2018.
4. Bardia A, Mayer IA, Diamond JR, et al: Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 35:2141-2148, 2017.
5. Kim SB, Dent R, Im SA, et al: Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 8:1360-1372, 2017.
6. Schmid P, Abraham J, Chan S, et al: Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: The PAKT trial. J Clin Oncol 38:423-433, 2020.
7. Vinayak S, Tolaney SM, Schwartzberg L, et al: Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol 5:1132-1140, 2019.
8. Domchek SM, Postel-Vinay S, Im SA, et al: Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): An open-label, multicentre, phase 1/2, basket study. Lancet Oncol 21:1155-1164, 2020.
9. Traina TA, Miller K, Yardley DA, et al: Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol 36:884-890, 2018.
10. Gucalp A, Boyle A, Alano T, et al: Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer. ASCO20 Virtual Scientific Program. Abstract 1017.