Molecular testing is becoming increasingly important for refining targeted treatment approaches for patients with hormone receptor–positive, HER2-negative metastatic breast cancer, a setting in which several agents have been recently approved and additional promising investigational regimens are poised to rapidly enhance the treatment paradigm, according to Kevin Kalinsky, MD, MS, FASCO.
“For as long as possible, we want patients to [receive] therapy that is well tolerated [and for which] they don’t have to spend time in infusion centers,” Kalinsky said in an interview with OncLive®.
In the interview, Kalinsky discussed the importance of optimizing well-tolerated endocrine-based therapies and delaying chemotherapy initiation in patients with hormone receptor–positive, HER2-negative metastatic breast cancer; the critical role of molecular testing in guiding post-CDK4/6 inhibitor treatment decisions; and ongoing challenges regarding treatment sequencing, drug availability, and patient adherence to endocrine therapies.
He highlighted the implications of findings from the final overall survival (OS) analysis of the phase 3 INAVO120 trial (NCT04191499), which were presented at the 2025 ASCO Annual Meeting. This study showed that first-line inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex; n = 161) significantly improved OS vs placebo plus palbociclib and fulvestrant (n = 164) in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer (HR, 0.67; 95% CI, 0.48-0.94; P = .0190).1
He also cited data that support the emerging treatment strategy of using a CDK4/6 inhibitor following prior progression on another agent in the same class. For instance, the phase 3 postMONARCH trial (NCT05169567) demonstrated that among patients with hormone receptor–positive, HER2-negative advanced breast cancer who had disease progression or recurrence following treatment with a prior CDK4/6 inhibitor (palbociclib, 58.8%; ribociclib [Kisqali], 33.5%; or abemaciclib [Verzenio], 7.7%) plus an aromatase inhibitor (AI), treatment with the CDK4/6 inhibitor abemaciclib in combination with fulvestrant (n = 182) significantly improved progression-free survival (PFS) vs placebo plus fulvestrant (n = 186; HR, 0.73; 95% CI, 0.57-0.95; P = .017).2
Kalinsky is a professor in and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine; as well as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and the director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia.
OncLive: Although CDK4/6 inhibitor–based regimens have demonstrated efficacy in the frontline setting for hormone receptor–positive breast cancer, what are some of the challenges and limitations of these combinations?
Kalinsky: Some of the challenges we face post-CDK4/6 inhibition are the development of resistance and trying to [offer] options that are endocrine based for patients. We have determined that the median time to the start of chemotherapy is important for our patients, because for estrogen receptor [ER]–positive disease, [treatment] is a marathon. It’s not a sprint. That’s the unmet need where the field is trying to continue to go for ER-positive, HER2-negative metastatic breast cancer.
What is the importance of testing for molecular alterations—including those in ESR1, PTEN, AKT, PIK3CA—at progression, or potentially before progression in the case of ESR1 mutations?
Given that we see ESR1 mutations [in] patients who’ve had tumors that have progressed on an AI, it is important to check for ESR1 mutations. We also see that approximately one-third of patients have alterations in the PI3K/AKT pathway. Those include PIK3CA mutations, AKT mutations, or alterations in PTEN. We have approvals of agents like capivasertib [Truqap] and alpelisib [(Piqray) for these patients], though we generally use capivasertib [more often] given its safety profile.
Additionally, we saw data at ASCO 2025 for patients with endocrine-resistant disease that has become newly metastatic. We’ve already seen the approval of inavolisib plus fulvestrant and palbociclib given the PFS advantage in patients who have endocrine-resistant disease, meaning [disease that has] progressed on an AI or within 12 months of completing [therapy with an AI] in the adjuvant setting. However, at ASCO, we saw an OS advantage [with the inavolisib-based combination], which is the first we’ve seen with an agent that targets that pathway. It is important to [see whether] patients have PI3K mutations [following AI progression].
Additionally, there are other targetable alterations, like germline PALB2 or BRCA [mutations]. [There is also a] question about [the efficacy of] PARP inhibition in patients with somatic BRCA or PALB2 [mutations]. It’s important to think about those considerations as well.
What are the key factors you consider for second-line therapy in patients with hormone receptor–positive breast cancer?
The factors that are important post-progression on an AI and a CDK4/6 inhibitor [include]: How long [was the patient receiving] their prior CDK4/6 inhibitor? Were they receiving it for more than 1 year?
[If a] patient has low-volume, bone-only disease, one may consider elacestrant [Orserdu]. If you have patients who have a PI3K mutation, you can consider fulvestrant plus capivasertib. Sometimes I consider giving doublet therapy in patients who need a bit more of a response. We also have fulvestrant plus everolimus [Afinitor]. Everolimus benefits patients regardless of PI3K mutation status or any alterations in that pathway; just make sure [patients use] the prophylactic oral rinse.
We also have data with [the use of] a CDK4/6 inhibitor [following a different] CDK4/6 inhibitor like abemaciclib plus fulvestrant based on the postMONARCH data [and] the phase 2 MAINTAIN study [NCT02632045] of fulvestrant plus ribociclib [in patients with hormone receptor–positive, HER2-negative advanced breast cancer]. We’ll see if we [gain] approval of other agents that we’ve seen [have] notable data, like imlunestrant plus abemaciclib from the phase 3 EMBER-3 trial [NCT04975308].
Although novel endocrine therapies have entered clinical practice for patients with hormone receptor–positive disease, what challenges still exist regarding the future of this treatment field?
Recently, we’ve seen impressive data with new drugs. Some of these drugs [are not] available at this moment. Regarding the phase 3 SERENA-6 trial [NCT04964934] regimen, for instance, we don’t have camizestrant available in the clinic. Regarding EMBER-3, we don’t have imlunestrant available in the clinic. Vepdegestrant is not available yet. We’re hoping to see whether they get approved. Important questions remain, like: What’s the best sequencing [approach]?
Also, some patients don’t tolerate some of the endocrine therapies we give. We see this in the early-stage setting too. Patients may have arthralgias, and they don’t tolerate these agents. We’ve been emphasizing that patients are not likely to benefit [from therapy] if they’re not taking the drugs. Those are some of the important considerations [based on] where we are post-ASCO 2025.
References
- Turner NC, Im SA, Saura C, et al. INAVO120: phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). J Clin Oncol. 2025;43(suppl 16):1003. doi:10.1200/JCO.2025.43.16_suppl.1003
- Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase III postMONARCH trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086