New Challenge in Triple-Negative Breast Cancer: Optimizing the Sequencing of Treatments

Get Permission

New approaches are offering hope for better outcomes in metastatic triple-negative breast cancer, according to Suchita Pakkala, MD, of Emory University’s Winship Cancer Institute, Atlanta. She shared her thoughts on using PARP inhibitors and antibody-drug conjugates at the 2023 Debates and Didactics in Hematology and Oncology Conference, sponsored annually by Winship, in Sea Island, Georgia.1

“The study [DESTINY-Breast04] got a standing ovation at the 2022 ASCO Annual Meeting, and for good reason.”
— Suchita Pakkala, MD

Tweet this quote

Dr. Pakkala noted the success of the checkpoint inhibitor pembrolizumab in this malignancy, which proved its value in KEYNOTE-355, especially in patients with a PD-L1 compositive positive score (CPS) of at least 10.2 In this subset of patients with triple-negative disease, median progression-free survival was 9.7 months vs 5.6 months (hazard ratio [HR] = 0.66), and median overall survival was 23.0 months vs 16.1 months (HR = 0.73; P = .0093).2 However, as Dr. Pakkala pointed out, at least half the triple-negative population lack a CPS of at least 10.

PARP Inhibitors

“We now have the option for all patients with metastatic breast cancer to qualify for germline testing, and about 5% of these patients will have BRCA1 or BRCA2 alterations,” Dr. Pakkala said. This qualifies patients for treatment with a PARP inhibitor in the second line or later, based on the results of the OlympiAD3 and the EMBRACA trials.4 In OlympiAD, treatment with olaparib improved progression-free survival as compared with treatment of physician’s choice or chemotherapy, but it did not significantly improve overall survival in the intent-to-treat population (HR = 0.88).

“That said, however, about 9% of patients remained on olaparib at 3 years compared with no patients on chemotherapy, and when you look at the group without prior chemotherapy, there was an overall survival improvement,” Dr. Pakkala pointed out. Median overall survival in that subset was 22.6 months with olaparib vs 14.7 months with chemotherapy (HR = 0.55; 95% confidence interval = 0.33–0.95). This finding suggests “that the earlier we use the PARP inhibitors, the better the response,” she maintained.

Similar findings came from EMBRACA, which also showed no improvement in overall survival with a PARP inhibitor compared with chemotherapy (HR = 0.85). However, she added, patients remained on talazoparib longer than chemotherapy and reported improvements in quality of life.

Are PARP inhibitors more effective when used in combination with immunotherapy? Not really, according to at least five trials that found no real boost in response rates, though longer durations of response have been observed, commented Dr. Pakkala.

Antibody-Drug Conjugates: Focus
on Sacituzumab Govitecan

Antibody-drug conjugates are a new option for metastatic triple-negative disease. They work by directly attacking and killing antigen-expressing cells in the tumor and through “bystander killing” of nearby antigen-negative cells. Sacituzumab govitecan-hziy is a topoisomerase-1 inhibitor targeting TROP-2, an antigen expressed in up to 90% of all breast cancers.

The drug was approved based on the ASCENT trial.5 In this study, median progression-free survival was significantly increased by 3.1 months with sacituzumab govitecan over chemotherapy (HR = 0.43) and overall survival by 4.9 months (HR = 0.51). Of note, these results are in a population previously treated with a median of four lines of therapy. Improvement was achieved regardless of TROP-2 expression, although patients with high or medium TROP-2 expression had somewhat greater numerical benefit, Dr. Pakkala said. Patients who received treatment in the second-line setting had particular benefit, with median progression-free survival of 5.7 months vs 1.5 months (HR = 0.41) and overall survival of 10.9 months vs 4.9 months (HR = 0.51).

“Again, similar to what we see with PARP inhibitors, the earlier we use these agents, the more effective they are,” she observed.

Antibody-Drug Conjugates in HER2-Low
Disease: Focus on T-DXd

HER2-low disease is a relatively new entity, defined as tumors that are HER2 immunohistochemistry (IHC) 1+ or 2+ but in situ hybridization–negative. HER2-low status is seen in about 45% to 55% of all breast cancers and in 37% of triple-negative tumors. Clinically and prognostically, these HER2-low tumors behave much like HER2-0 tumors.

“Patients may derive a benefit from an antibody-drug conjugate after disease progression on a similar agent in the class.”
— Suchita Pakkala, MD

Tweet this quote

In the landmark DESTINY-Breast04 trial of patients with HER2-low, mostly hormone receptor–positive disease and one to two prior lines of chemotherapy, the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd), a topoisomerase-1 inhibitor, significantly improved overall survival over treatment of physician’s choice.6 “The study got a standing ovation at the 2022 ASCO Annual Meeting, and for good reason,” Dr. Pakkala commented.

In the subset of 58 patients with triple-negative disease, median progression-free survival increased by 5.6 months (HR = 0.46). Overall survival was boosted by 9.9 months (HR = 0.48), reaching 18.2 months with T-DXd as compared with 8.3 months with chemotherapy.

Other HER-Targeting
Antibody-Drug Conjugates

A newer TROP-2–targeted antibody-drug conjugate with a topoisomerase-1 payload is datopotamab-deruxtecan (Dato-DXd). Dato-DXd was studied in the phase I TROPION-PanTumor01 study; in this trial, 44 heavily pretreated patients with triple-negative breast cancer had a response rate of 32%, rising to 44% among those naive to topoisomerase-1 inhibitors.7 In the overall population, median progression-free survival was 4.4 months, median overall survival was 13.5 months, and median duration of response was 16.8 months.

Responses were seen among the one-third of patients with prior exposure to another topoisomerase-1 inhibitor–based antibody-drug conjugate, which Dr. Pakkala believes is encouraging. This finding suggests that patients may derive a benefit from an antibody-drug conjugate after disease progression on a similar agent in the class, she added.

Another new HER2-targeting antibody-drug conjugate is patritumab deruxtecan, which produced responses in 35% of patients in the phase II BRE354 study.8 About half the patients remained on treatment for 6 months, and activity was seen regardless of HER2 expression, she noted.

Sequencing of Antibody-Drug Conjugates

With several antibody-drug conjugates approved and others emerging for the treatment of metastatic triple-negative breast cancer, many patients are becoming candidates for multiple agents. However, given the potential for cross-resistance, the optimal sequencing of these therapies is unknown.

A single-institution study presented at the 2023 ASCO Annual Meeting looked at various sequencing strategies in 35 patients, 20 of whom had triple-negative breast cancer.9 In the triple-negative subset, median progression-free survival was 8.2 months after treatment with the first antibody-drug conjugate and 3.0 months after treatment with a different one in the second line. The researchers found that progression-free survival was longer when the second drug had a different antibody target from the first one. When the second antibody-drug conjugate contained the same target as the first one, cross-resistance was more likely.

As for specific treatment sequence, in the hormone receptor–positive subset, T-DXd given first and sacituzumab govitecan given second appeared to be the more effective approach; however, in the triple-negative subset, the best sequence was not clear. In general, the findings suggest that changing the antibody target for the second therapy may decrease the risk for cross-resistance, she said.

Proposed Algorithm

According to Dr. Pakkala’s approach to the treatment of metastatic triple-negative breast cancer, the first consideration is the patient’s PD-L1 expression. For patients with a CPS of at least 10, she opts for pembrolizumab plus chemotherapy, whereas for those with a CPS less than 10, she considers BRCA mutation status in choosing treatment, as follows:

  • BRCA-mutated: If the patient with BRCA alteration has received prior chemotherapy, prescribe a PARP inhibitor (currently approved only after chemotherapy). If the patient with BRCA alteration has not had chemotherapy, initiate first-line chemotherapy, either taxane-based or platinum-based (platinum is preferred).
  • Non–BRCA-mutated: Prescribe first-line chemotherapy, either taxane-based or platinum-based (platinum is preferred).

In the second-line or later setting, multiple options include the following agents:

  • Sacituzumab govitecan (after two prior lines, one being metastatic)
  • T-DXd (for HER2-low disease)
  • Pembrolizumab (no prior immunotherapy, high tumor mutation burden or microsatellite instability–high or mismatch repair–deficient tumor)
  • Entrectinib or larotrectinib (NTRK fusion)
  • Selpercatinib (RET fusion)
  • Dabrafenib plus trametinib (BRAF V600E mutation)
  • Single-agent chemotherapy: eribulin, capecitabine, gemcitabine, vinorelbine.

Trials Underway

Several important trials are evaluating combinations of the agents Dr. Pakkala described. ASCENT-04 is comparing sacituzumab govitecan plus pembrolizumab, vs chemotherapy plus pembrolizumab, as a first-line treatment of metastatic PD-L1–positive triple-negative breast cancer. DESTINY-Breast06 is evaluating T-DXd vs chemotherapy in HER2 IHC 0 (ie, “ultra-low”), and HER2 1+ and 2+ patients, after two prior lines of endocrine therapy. TRADE-DXd is evaluating different sequences of T-DXd and Dato-DXd in patients with HER2-low tumors who are either hormone receptor–negative or –positive. 

DISCLOSURE: Dr. Pakkala reported no conflicts of interest.


1. Pakkala S: Metastatic triple-negative breast cancer: Sequencing immunotherapy, PARP inhibitors, and antibody-drug conjugates. 2023 Debates and Didactics in Hematology and Oncology. Presented July 23, 2023.

2. Rugo HS, Cortés J, Cescon DW, et al: KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. ESMO Congress 2021. Abstract LBA16. Presented September 19, 2021.

3. Robson ME, Im SA, Senkus E, et al: OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Eur J Cancer 184:39-47, 2023.

4. 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.

5. Bardia A, Hurvitz SA, Tolaney SM et al: Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529-1541, 2021.

6. Modi S, Jacot W, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9-20, 2022.

7. Bardia A, Krop I, Meric-Bernstam F, et al: Datopotamab deruxtecan (Dato-DXd) in advanced triple-negative breast cancer: Updated results from the phase 1 TROPION-PanTumor01 study. 2022 San Antonio Breast Cancer Symposium. Abstract P6-10-03. Presented December 9, 2022.

8. Hamilton EP, Dosunmu O, Shastry M, et al: A phase 2 study of HER3-DXd in patients with metastatic breast cancer. 2023 ASCO Annual Meeting. Abstract 1004. Presented June 5, 2023.

9. Abelman RO, Spring L, Fell GG, et al: Sequential use of antibody-drug conjugate after antibody-drug conjugate for patients with metastatic breast cancer: ADC after ADC (A3) study. 2023 ASCO Annual Meeting. Abstract 1022. Presented June 4, 2023.