Matthew P. Goetz, MD, explores first-line treatment selection, emerging targeted therapies, and unmet sequencing needs in metastatic breast cancer.
Selecting and sequencing targeted therapies for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer requires consideration of survival data from pivotal trials, the endocrine sensitivity molecular alterations in individual tumors, and treatment tolerability, according to Matthew P. Goetz, MD. He added that improving disease control after endocrine therapy resistance develops remains a major unmet need, despite the expanding range of targeted treatment options.
In an interview with OncLive®, Goetz discussed factors guiding first-line CDK4/6 inhibitor selection, the impact of additional targeted therapies on treatment sequencing decisions, and emerging strategies for managing endocrine therapy–resistant disease. He highlighted PI3K pathway inhibitors, oral selective estrogen receptor degraders (SERDs), and newer approaches to CDK4 and CDK6 targeting, including questions about combining therapies when ESR1 and PIK3CA mutations co-exist.
Goetz is a professor of oncology and pharmacology and the enterprise deputy director for translational research at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.
Goetz: In the first-line setting, the CDK4/6 inhibitors have become the standard of care [SOC]. Over the past 10 years, we have [found that] the CDK4/6 inhibitors ribociclib [Kisqali] and abemaciclib [Verzenio] prolong survival. The ribociclib data are consistent across both premenopausal and postmenopausal patients in the first- and second-line settings.
The data with abemaciclib are a little less consistent. In the first-line setting, the phase 3 MONARCH 3 trial [NCT02246621] did not lead to an improvement in overall survival [(OS) with abemaciclib plus a nonsteroidal aromatase inhibitor vs placebo plus a nonsteroidal aromatase inhibitor]. [The data were] close, but [the OS difference] didn’t quite meet statistical significance. The [OS] hazard ratio was similar to [those seen in] trials with ribociclib, and perhaps the [MONARCH 3] trial was small and underpowered, and that was the reason for the lack of an OS difference.
However, the data with ribociclib [show] consistent improvements in OS. But, in the data with palbociclib [Ibrance], we see a consistent lack of improvement in OS. We don’t see a benefit with palbociclib in the adjuvant setting. CDK4/6 inhibitors are a SOC approach, and combining these drugs with, for example, an aromatase inhibitor, would be the standard approach.
Another major question has been: If we have patients with more concerning clinical features—for example, extensive visceral, liver, or lung involvement—should be giving chemotherapy first, and then the CDK4/6 inhibitor? The data have suggested that there’s no benefit of using chemotherapy first, followed by endocrine therapy. In fact, chemotherapy might be an inferior treatment approach for those patients.
There are some patients for whom we still use chemotherapy for a short period, and those are patients who are in true visceral crisis. But for the great majority of patients, CDK4/6 inhibitors plus hormonal therapy would be considered the standard approach.
One of the major questions people have had is: If you are using a CDK4/6 inhibitor, since we know, for example, that oral SERDs appear to be superior to aromatase inhibitors, would it be of value to swap out the aromatase inhibitor and use an oral SERD? This was first tested years ago with the [phase 2 PARSIFAL trial (NCT02491983)] that compared fulvestrant [Faslodex] plus palbociclib vs an aromatase inhibitor plus palbociclib. This trial demonstrated no benefit of using fulvestrant, an older SERD. But, [newer-generation] oral SERDs [may be] slightly better.
We’ve been waiting on data using the oral SERD giredestrant in combination with a CDK4/6 inhibitor in the phase 3 persevERA Breast Cancer trial [NCT04546009]. These data were presented at the
Metastatic HR-Positive, HER2-Negative Breast Cancer Management
[In September 2026, we saw a]
If we’re going to give a CDK4/6 inhibitor in the first-line setting, there is no PFS advantage for using an oral SERD. There could be some tolerability [benefits] and perhaps some quality-of-life [benefits], but nothing that will probably lead to an FDA approval for that class of drugs in combination with a CDK4/6 inhibitor.
Regarding PIK3CA mutations and alterations in the PI3K pathway, we have alpelisib [Vijoice] that’s approved in the second-line setting. We also have the drug capivasertib [Truqap], which is an AKT inhibitor. We also have data with inavolisib [Itovebi], and that was tested in [the phase 3 INAVO120 trial (NCT04191499)] in combination with [fulvestrant] and palbociclib in the metastatic setting in patients who had progressed relatively quickly in the adjuvant setting. In that trial, there seemed to be a benefit with inavolisib in combination with the CDK4/6 inhibitor palbociclib and [fulvestrant] over palbociclib and endocrine therapy alone.
For the [INAVO120] trial, there were some questions that many of us have wondered about. First, the patients in the control arm did not get treated with a PI3K inhibitor, an AKT inhibitor, or even an mTOR inhibitor. Therefore, it’s hard to know the benefit of inavolisib vs those SOC approaches. Many of us would also note that the drug alpelisib is poorly tolerated. Many of our patients are not candidates for that drug.
The allosteric inhibitors are looking exciting. These are drugs that target the PI3K pathway but appear to be associated with fewer adverse effects, such as hyperglycemia. We have some important phase 3 trials that are ongoing, testing these allosteric inhibitors in patients who have PIK3CA mutations.
There are other targeted drugs that are being tested, and those are medications that we’re beginning to see some data for. We’re also beginning to see next generations of CDK4/6 inhibitors. We’re also seeing more of the selective CDK4 inhibitors, such as atirmociclib [PF-07220060]. Additionally, we’re seeing data with CDK4/6 proteolysis-targeting chimeras [(PROTACs), which are different than SERDs targeting] the estrogen receptor [ER]. [One] PROTAC, BTX-9341, is targeting CDK4/6 for degradation, whereas other drugs are kinase inhibitors. We’re excited to see what happens when you degrade CDK4 and CDK6, especially CDK6, since CDK6 appears to be an escape mechanism.
In the first-line setting, patients with endocrine-sensitive disease, especially de novo disease, or a long treatment-free interval after completing adjuvant endocrine therapy, do well on a CDK4/6 inhibitor plus endocrine therapy. But in general, a major unmet need is the development of new approaches for these patients with endocrine-resistant disease. One of the drugs that looks exciting is gedatolisib [Revtorpyk], which was
For patients who have become resistant to standard CDK4/6 inhibitors, what is the best approach for treatment? What is the best sequence? Should we use a drug like gedatolisib first? Should we wait and use it after progression on, for example, an oral allosteric PI3K inhibitor?
Another question relates to the sequence of these drugs in patients who have ESR1 mutations. Should we use these drugs sequentially? If we see both an ESR1 mutation and a PIK3CA mutation, should we be co-targeting? A lot of us think we should be co-targeting in that situation, for example, using a drug like imlunestrant [Inluriyo] that is a potent targeter of the ER, along with a drug that targets the PI3K pathway.
These are questions that are important. But in general, if you look at even these targeted drugs that we are excited about, they’re having relatively modest effects [lasting approximately] 5 to 10 months. We would like to have better therapies to target these patients, because otherwise what we then move on to is chemotherapy. Antibody-drug conjugates [ADCs] are exciting. We’re all excited about ADCs, but at the end of the day, ADCs are chemotherapy. The consideration for new and better targeted approaches for treating patients with ER-positive [breast cancer] that will allow us to delay chemotherapy is going to be a major focus over the next 10 to 15 years.
