Novel Anti-Estrogen Therapies Are Poised to Expand Treatment Options in Advanced ER+ Breast Cancer

Novel anti-estrogen therapies could expand the treatment paradigm following CDK4/6 inhibitor–based therapies for patients with estrogen receptor (ER)–positive advanced breast cancer, according to Seth Wander, MD, PhD, who added that identifying specific subgroups who may benefit most from certain therapies or combinations will also bring a more personalized treatment approach to this space.

“There are amazing opportunities, both in clinical trials right now and soon in standard practice, across the spectrum with these agents, and there'll be a lot more to discuss in the coming months and years,” Wander said.

One such novel agent is the PI3K pathway inhibitor inavolisib (GDC-0077), which is being investigated in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer following progression on adjuvant endocrine therapy in the phase 3 INAVO120 trial (NCT04191499).

Primary data from the study showed that patients treated with the triplet experienced a median progression-free survival of 15.0 months vs 7.3 months for those given palbociclib and fulvestrant alone (HR, 0.43; 95% CI, 0.32-0.59; P < .0001).¹ Updated findings from the study presented at the 2024 ASCO Annual Meeting demonstrated that the median time from randomization to end of next-line treatment was 24.0 months for the inavolisib arm vs 15.1 months in the palbociclib/fulvestrant arm (HR, 0.54; 95% CI, 0.38-0.77).²

In an interview with OncLive^®, Wander delved into the present limitations of current standard-of-care approaches in the metastatic ER–positive breast cancer and expanded on the utility of novel anti-estrogen therapies under investigation for this patient population.

Wander serves as an instructor in medicine at Harvard Medical School, as well as a medical oncologist at the Massachusetts General Hospital in Boston.

OncLive: What are the present limitations of frontline therapy in patients with ER-positive metastatic breast cancer? How have we seen novel endocrine therapies help bridge that gap?

Wander: We've come a tremendously far way in the last several years in developing better novel frontline agents for hormone receptor–positive metastatic breast cancer. Broadly speaking, the standard of care would now incorporate an aromatase inhibitor with a CDK4/6 inhibitor, and many folks prioritize the use of ribociclib [Kisqali] in this setting, based upon statistically significant, positive overall survival data in the first-line setting.

There are still some areas where we can improve in both directions. On one end of the spectrum, we have a subgroup of patients who might have more aggressive disease in that first-line, metastatic setting. These are patients, for example, who may progress on or shortly after adjuvant anti-estrogen therapy. They may also have progressed on adjuvant CDK4/6 inhibitor therapy, as we have 2 drugs—abemaciclib [Verzenio] and ribociclib—recently FDA-approved in that space. That represents a critically important population for us to be looking at.

In the past year, we saw data from the INAVO120 study in that population; patients with higher-risk disease that progressed on adjuvant anti-estrogen-based therapy and harbored a PIK3CA mutation did better with a triplet combination of fulvestrant with palbociclib and the novel PI3K inhibitor, inavolisib. We need to develop better strategies for these higher-risk, endocrine-refractory patients who are progressing through our emerging adjuvant treatment regimens.

On the other end of the spectrum, I believe most clinicians would agree that there may be a subset of patients with slower-growing, indolent, maybe oligometastatic or bone-only, hormone receptor–positive breast cancer, [and these patients] may benefit from avoiding the CDK4/6 inhibitor [in the first-line metastatic setting] due to both financial and physical toxicities. There are probably some patients who have disease that would be well controlled just on anti-estrogen therapy alone.

One of the key unmet needs here is understanding how this population is spreading out across this spectrum. Who may be able to get away with endocrine therapy alone? Who needs more aggressive up-front therapy, even with a triplet combination? Who the right patients are for the current standard of care with an aromatase inhibitor and a CDK4/6 inhibitor? We are developing new strategies across this population, and we also need to work on developing better biomarker approaches.

How are you currently approaching these patients in clinical practice without definitive data telling you which approach is better for different subgroups of patients?

In my own practice, right now, for the vast majority of patients who may have untreated hormone receptor–positive metastatic breast cancer or had a recurrence and have been off anti-estrogen therapy for a prolonged period of time, I am using the standard frontline regimen with an aromatase inhibitor and a CDK4/6 inhibitor. For the reasons we just discussed, I typically utilize ribociclib in this patient population.

For those patients who have more aggressive disease that has progressed on or shortly after their adjuvant anti-estrogen therapy, we're looking at clinical trial opportunities in this space with novel anti-estrogen agents, novel targeted agents, and combinations. We need to focus on that smaller subgroup of patients who probably have a worse prognosis on standard frontline therapy. Today, the current standard of care—pending updates and approval from the INAVO120 study—would be fulvestrant with a CDK4/6 inhibitor. Here, you can probably choose amongst the different CDK4/6 inhibitors in combination with fulvestrant, based on second-line metastatic data.

However, we need to do better in this population. This is where getting genomic sequencing becomes important to understanding if a patient has, for example, PI3K pathway alterations and may be candidates for alpelisib [Vijoice] or capivasertib [Truqap]; whether patients have ESR1 alterations and may be candidates for novel next-generation anti-estrogen agents; or whether patients have alterations in other targets and pathways [where there] might not yet be standard-of-care [agents], but we may have clinical trial opportunities. These patients might have RAS alterations or other pathway alterations. In the future, we'll have opportunities for [targeting] all those pathways that are under active clinical development right now.

In terms of novel anti-estrogen therapies, what are the different approaches that fit within that category?

This is an exciting topic, and the field is rapidly shifting beneath our feet. There is a large spectrum of next-generation, novel anti-estrogen agents under active clinical development, everywhere from phase 1 through phase 3 [trials], both as single agents and in combinations with various partner agents. [Partner agents for these combinations] are typically targeted therapies, CDK4/6 inhibitors, or next-generation CDK4/2 inhibitors.

Broadly speaking, you can divide these next-generation, anti-estrogen agents into several categories. The most common agent that we're using right now would be an oral selective estrogen receptor degrader [SERD]. We saw the first FDA approval of an oral SERD in elacestrant [Orserdu] based upon the phase 3 EMERALD trial [NCT03778931].

There are a few other drugs in active clinical development from a variety of companies, and we've started to see phase 2 and, soon, phase 3 data. We've seen some mixed results here. Some agents have failed to show benefit in some of these later studies. Other agents seem to do okay as single-agent therapy, but perhaps they might be better suited in a specific subpopulation, for example, [patients harboring] ESR1 mutations; or perhaps [these agents are better suited] in combination with another targeted therapy.

We have oral SERDS moving along, with many of them in late-phase clinical development, both alone and in combinations. Then we have other innovative next-generation, anti-estrogen agents, such as selective estrogen receptor modulators [SERMs], proteolysis-targeting chimeras [PROTACs], and covalent ER antagonists.

There are many different drugs within clinical development across these categories that act through slightly different mechanisms. For example, SERMs act similarly to what we've seen with tamoxifen by modulating the activity of the ER differently in different tissues. PROTACs use the cellular machinery of ubiquitination to target the ER for more efficient and complete degradation. We also have covalent ER blockers. Some drugs also have properties spanning multiple categories.

These agents have shown tremendous promise in preclinical studies and early-phase clinical trials, and now we're starting to see larger patient cohorts being treated. There are lots of exciting opportunities coming up; the future challenge as these drugs continue to enter clinical practice will be to understand which patients get the most benefit from these [different] categories [of agents].

Can we learn something about the clinical parameters or the genomic and molecular features of the cancer to decide if a patient might be better with a SERD or if another patient might be better with a PROTAC? Which patients could do okay with one of these agents as monotherapy vs which patients might need a combination? What should that combination be? Is it with a first-generation CDK4/6 inhibitor, a next-generation CDK4/2 inhibitor, a PI3K pathway inhibitor, a RAS pathway inhibitor, or [something else]?

References

1. Jhaveri KL, Im S-A, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. Presented at San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS03-13.
2. Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2‑negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 Phase III randomized trial additional analyses. J Clin Oncol. 2024;42 (suppl 16):1003. Doi: 10.1200/JCO.2024.42.16_suppl.1003.