Optimizing Therapy Sequencing in HR+/HER2- or Triple-Negative Breast Cancer

Jade E. Jones, MD, spotlighted ongoing clinical advances in endocrine therapies, particularly with emergent oral selective estrogen receptor degraders, which may give more options and greater efficacy for patients.

In a conversation with CancerNetwork®, Jade E. Jones, MD, assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and medical oncologist at the Emory Winship Cancer Institute, discussed therapy options for patients with hormone receptor (HR)–positive, HER2-negative breast cancers, as well as those with triple-negative breast cancer (TNBC).

Initially, Jones discussed the use of PARP inhibition for patients with germline mutations, explaining that clinical outcomes were improved with olaparib (Lynparza) or talazoparib (Talzenna) in patients with germline BRCA-mutant disease, with emerging data supporting their use in somatic mutations. She expressed considering their use for patients with HR-positive disease or TNBC who want an oral option after progressing on endocrine therapy, among other indications, but highlighted that ongoing clinical trials are elucidating their efficacy.

Additionally, a comparison between fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy) was explored, with data from the phase 3 DESTINY-Breast04 (NCT03734029) and phase 3 TROPiCS-02 (NCT03901339) studies showing that T-DXd elicited favorable survival outcomes in HR-positive disease and sacituzumab govitecan showed favorable outcomes in TNBC, respectively.^1,2 Furthermore, Jones discussed strategies for sequencing these antibody-drug conjugates (ADCs), highlighting considerations for HER2-signaling and the presence of TROP2 overexpression. She further touched upon the need to elucidate endocrine sensitivity in patients who progressed following CDK4/6 inhibition to discern next treatment steps.

Jones concluded by discussing the next steps for improving outcomes among patients with TNBC or HR-positive disease, covering a need to develop ADCs with different targets. She further spotlighted ongoing clinical advances in endocrine therapies, particularly with emergent oral selective estrogen receptor degraders (SERDs), which may give more options and greater efficacy for patients. Finally, she expressed excitement for new endocrine therapy options and reiterated a need to expand the ADC portfolio to target a greater number of biomarkers.

CancerNetwork: How should clinicians interpret and act upon somatic BRCA mutations identified through liquid biopsies in the context of treatment selection for patients with metastatic breast?

Jones: There are data for how we use PARP inhibitors for germline mutations. That was our trial where we…used olaparib or talazoparib, and showed improvement in clinical outcomes, specifically people who had inherited [BRCA2 and BRCA1] mutations. However, there are also data to support that these mutations may also respond to PARP inhibitors for people who have somatic [mutations]. Technically, it’s not written in the guidelines to use these drugs, but there are clinical trials—and I’ve sent my patients for clinical trials—where if patients have these mutations, they’re receiving PARP inhibitors.

I would say if you have a patient who has HR-positive [disease], have exhausted their endocrine therapy but are still wanting an oral option, or [have] triple-negative [disease] and tend to be more chemotherapy-resistant or had an ADC, then you’re trying to get a drug that may be a bit more targeted for those patients and to consider a PARP inhibitor. If there is a clinical trial, I would try to get them on [one] where we’re using the PARP inhibitor.

There’s a role for PARP inhibitors in somatic BRCA mutations. A lot of this is being done in clinical trials, but there are data to support that there are some patients who will respond to PARP inhibitors in this case.

How did the efficacy and safety profiles of sacituzumab govitecan and T-DXd compare in the treatment of HR-positive, HER2-negative disease as well as TNBC based on recent trial data?

Jones: I’m excited that we have these new ADCs, and both have shown to be effective in [HR-positive, HER2-negative and TNBC] populations. But in terms of which one we’re giving these drugs to, we have to go to the data, who was on the trial, and where they were treated. In the phase 3 DESTINY-Breast04 study, where T-DXd was given to [patients with] predominantly HR-positive [disease]—but a small [TNBC] population, about 25%—we saw a significant improvement in progression-free survival [PFS] over standard chemotherapy.

In terms of the TROPiCS-02 studies, which showed sacituzumab govitecan could be effective in [patients with] HR-positive [disease], we also have data to support them in the TNBC population. For sacituzumab govitecan in [patients with] HR-positive [disease], the PFS wasn’t as long as with T-DXd, but they were more heavily treated. For the most part, most people are using T-DXd first in our HR-positive [patients], but they can still get sacituzumab govitecan.

In the [TNBC population], there are so much more data for sacituzumab govitecan. For the most part, people are using sacituzumab govitecan first for our [patients with] TNBC, but they can still get T-DXd later in their treatment.

Considering the recent TROPiCS-02 and DESTINY-Breast06 trial data, what are some of the key takeaways regarding the sequencing of ADCs in HR-positive, HER2-negative disease and TNBC?

First, you [must] make sure that for [HER2-expressing patients], that they have this signal. They [must] either be HER2-low or ultra-low. That is a lot of patients, but there are still patients who have HER2-negative [disease] who do not qualify for that drug. Therefore, if they do not qualify for the drug, sacituzumab govitecan should be the option for the HR-positive patients. TROP2 was found on these studies to be responsive whether the TROP2 was high or low. In general, we are not testing for TROP2, but we are offering that drug to all our patients.

In an HR-positive [patient], if they’re HER2-low or ultra-low, I’m probably going to give T-DXd first and may use sacituzumab govitecan later in my patients with [TNBC] just because there are more clinical data. In my [patients with] TNBC, I’m going to use TROP2 [therapy] first because it doesn’t require them to be HER2-low or ultra-low, and we have good data in terms of the PFS in those patients.

In patients with HR-positive, HER2-negative metastatic breast cancer who are progressing on those CDK4/6 inhibitors, what factors influence the decision-making process between using either T-DXd or sacituzumab govitecan?

Jones: When we’re talking about after a patient comes off their first-line therapy with a CDK4/6 inhibitor plus endocrine therapy, the question is: “Are they endocrine sensitive, or are they endocrine resistant?” Most patients like being on endocrine therapy options over chemotherapy and even over ADCs, and that’s because they tend to be better tolerated, [and] most of them are oral and require the patient to be at home more often than being in the infusion center.

My real decision [includes] 2 things I factor in. One, how long was the patient on their first-line therapy? We have multiple trials that show if you’re only on endocrine therapy for 6 months or less, then [you’re] likely not going to [respond] to the next line of endocrine therapy, and you tend to have a more aggressive disease. The other [factor] is the burden of disease––[does] this patient [have] a large volume of disease, and are they not even on the endocrine therapy for that long?

[For] that aspect, I probably need to switch over to a chemotherapy or ADC option; more likely an ADC because the patient may not have a lot of time to figure out if they’re going to respond, and they may be endocrine resistant. My main focus is how long they were on that endocrine therapy and [whether] I think other forms of endocrine therapy would benefit that patient. [Those] are my main decision-makers.

Looking ahead, what are the next steps for improving outcomes in this patient population?

Jones: If we’re talking about ADCs, [the next step] is getting better at our payload. For sacituzumab govitecan and T-DXd, they have the same payload. By payload, I mean the same chemotherapy, but with a different target. [The] sacituzumab govitecan target is TROP2, and then T-DXd’s target is HER2. If we can have more ADCs come out that have different targets and even different types of payloads or chemotherapy, then maybe we can evolve [these therapies] to [treat] these patients with even better ADCs. [If] they progress on the first one, maybe they’ll still be responsive to the second one.

Right now, we don’t have a randomized [clinical] trial to show this, but retrospective data do suggest that you do not get as much of a response to the second approved ADC as you do to the first one. If you got sacituzumab govitecan first, you may [not] respond to [subsequent] T-DXd. I have had patients who respond to both, but it’s not going to be as long as if you had gotten T-DXd first, or vice versa. If you get T-DXd first, and then you get sacituzumab govitecan second, you may not have a significant response after. This is where I’m saying, “Well, maybe we need a different form of the payload.”

Exciting things are happening in terms of endocrine therapies. At the 2024 San Antonio Breast Cancer Symposium as well as the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, we’re seeing all these new oral SERDs that will likely come to market––giredestrant [GDC 9545] and camizestrant are drugs that will give patients further options in terms of endocrine therapies that seem, based on the data now, to be responsive in people who have resistant mutations, like ESR1. That may allow us to say, “Keep these patients on their endocrine therapies [longer], and then use the ADCs further along.”

[One takeaway] in this patient population is having these new, exciting endocrine therapies that tend to be well tolerated. And then [the second takeaway is] expanding our ADC portfolio. We currently have 3 ADCs [approved] for our HR-positive [population] and 2 for our TNBC [population]. I’m hoping that as new drugs, novel targets, and novel payloads come out, we’ll have even more to offer patients.

References

1. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients with HER2-low unresectable and/or metastatic breast cancer: updated survival results of the randomized, phase 3 DESTINY-Breast04 study. Ann Oncol. 2023;34(suppl 2):334-335. doi:10.1016/j.annonc.2023.09.553
2. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. The Lancet. Published online August 23, 2023. doi:10.1016/S0140-6736(23)01245-X