Jason A. Mouabbi, MD Efforts leveraging targets implicated in CDK 4/6 resistance for patients with hormone receptor (HR)–positive, HER2-negative breast cancer have resulted in the development of several up-and-coming classes of endocrine therapies along with the optimization of targeted therapies, according to Jason A. Mouabbi, MD.
“There have been a lot of advances recently, and what I call a ‘big bang’ of novel endocrine therapies are going to come to the market [soon],” Mouabbi said in an interview with OncLive ® regarding a State of the Science SummitTM on breast cancer, which he chaired. In the interview, Mouabbi highlighted ongoing research to integrate newer endocrine therapies into the armamentarium for first-line HR-positive breast cancer, such as selective estrogen receptor degraders (SERDs) including elacestrant (Orserdu) and camizestrant. Elacestrant gained FDA approval in 2023 based on positive data from the phase 3 EMERALD trial (NCT03778931).
1 Camizestrant is currently being evaluated in the phase 1 SERENA-1 trial (NCT03616587) and in additional SERENA trials in combination therapy approaches, after demonstrating superior progression-free survival outcomes vs fulvestrant (Faslodex) in the phase 2 SERENA-2 trial (NCT04214288). 2 Mouabbi also discussed early data with other emerging drug classes, including complete estrogen receptor antagonists (CERANs), proteolysis-targeting chimeras (PROTACs), and selective CDK4 inhibitors. One such PROTAC, vepdegestrant (ARV-471), received FDA fast track designation in February 2024, and is being investigated as both monotherapy in the second line and in combination with palbociclib (Ibrance) in the first line.
3,4 According to updated data from a phase 1b trial (NCT04072952), vepdegestrant plus palbociclib demonstrated a clinical benefit rate of 63.0% (95% CI, 47.5%-76.
8%) in patients withheavily pretreated locally advanced or metastatic estrogen receptor (ER)–positive HER2-negative breast cancer. 4 Mouabbi is an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in Houston. Mouabbi: The majority of breast cancers, [approximately] 70%, are HR-positive.
Because we consider the disease to be hormone-sensitive early on, the first few lines of therapies [for patients with HR-positive disease] always [include] an endocrine therapy, which targets the hormonal pathway, in combination with a targeted therapy. Endocrine therapies [such as] aromatase inhibitors or fulvestrant have been around for a long time. We’ve been improving on the targeted therapy front with the introduction of CDK4/6 inhibitors, PI3K-targeted agents, mTOR inhibitors, and so forth.
We’ve been heavily focusing on targeted therapy, but it’s also important to optimize the endocrine therapies. This is the heavy lift at the end of the day, targeting the hormonal pathway. [These novel endocrine therapies] come in different forms and have different modes of action.
One that was recently FDA approved is elacestrant, based on [data from] the EMERALD trial. However, the FDA narrowed that approval to patients [with HER2-negative disease] who acquired an ESR1 mutation [following progression on endocrine therapy.] [Accordingly,] there is a need for more agents.
The problem with fulvestrant is that it’s an intramuscular injection, so you are limited with the amount of medication you can administer [to patients]. The idea of having a pill is excellent, there is no limit how much we can give, so we can optimize the dose for our patients. [Our ability to do this is] improving.
When they compared, for example, elacestrant to fulvestrant, elacestrant pulled ahead [in terms of outcomes]. A similar [trend was observed] when we looked another oral SERD not yet approved, called camizestrant. When compared with fulvestrant, it came ahead.
[This was] especially [evident] in patients with ESR1 mutations, but also in the intention-to-treat population that included patients with or without the mutation. [Overall, this drug class is] very exciting because they are an oral formulation at a more optimal dose than the injectable that we’ve been using historically. There are other exciting drugs with different modes of action.
Before, we [were developing] SERDs. Now, we have complete ER antagonists, or CERANs. This is a more powerful inhibitor of the ER that also leads to degradation.
There is one drug currently in development called palazestrant [OP-1250]. This agent is very exciting and coming down the pipeline. [Another class of agents] of special interest are PROTACs.
These are also considered endocrine therapy, but they work by flagging ERs for degradation and is recycled by the cell machinery. The beauty of the PROTAC [agent] vepdegestrant is that the drug itself gets recycled [to then bind to additional ER target proteins]. Historically, drugs act 1 to 1.
For example, each molecule of fulvestrant will target one molecule of the ER. [After the receptor is degraded, that] fulvestrant molecule is completely gone. The idea with PROTACs is that once it flags an ER for degradation, the same molecule can go and flag another ER.
Because 1 molecule can target multiple ERs, [this drug is likely] going to be more powerful. Since we may not need as much of the drug to get the full effect, the adverse effect [AE] profiles [may improve]. These are some of the drugs that improve on the endocrine therapies.
[In her presentation at the SOSS, my colleague] Polly Niravath, MD, placed a large emphasis on also optimizing the targeted therapy that we usually combine with endocrine therapies. Currently, it is well established to use a CDK4/6 inhibitor in breast cancer in the first line. We want to inhibit CDK4 more than CDK6; in fact, inhibiting CDK6 is what gives us the main AE [associated with] those drugs, which is decreased white blood cell count.
If we can [develop a] drug that specifically targets CDK4 and spares CDK6, we could administer a higher dose that more optimally inhibits CDK4. There is currently a drug in early development, [PF-07220060, that could do just that]. Data presented showed that this drug is very active.
In that study, which is an early-phase, [first-in-human, phase 1/2] study [NCT04557449], all patients [with advanced solid tumors enriched for HR-positive, HER2-negative breast cancer had previously received a CDK4/6 inhibitor]. Even after CDK4/6 inhibition, those given a selective CDK4 inhibitor [achieved] impressive objective response rates and clinical responses. This is a very exciting drug.
The other thing we are trying to optimize is CDK2 inhibition. [Indirect inhibition of] CDK2 is one of the mechanisms of resistance to CDK4/6 inhibition, and adding a CDK2 inhibitor to a CDK4/6 inhibitor could [therefore] overcome that mechanism of resistance and restore sensitivity to CDK4/6 inhibitors. That’s another [drug class] currently in development.
Post-CDK4/6 inhibition, there is no standard of care [SOC]. Many key opinion leaders will propose [treatment] algorithms, and a lot of people follow them as being a SOC, but there is no [agreed-upon approach.] Each patient will have different characteristics, and you need to tailor therapy for each patient.
It is a generally accepted rule that as long as the patient’s tumor is still hormone sensitive, you first want to exhaust all your endocrine therapies prior to proceeding to antibody-drug conjugates or chemotherapy. For that reason, once a patient progresses on first-line endocrine therapy with a CDK4/6 inhibitor, we want to see if we can give them another endocrine therapy plus targeted therapy. Which one to administer all depends on the mutational analysis of the patient’s tumor at that moment in time.
[For example], patients with ESR1 mutations can go on to receive elacestrant, and patients who have a PI3KCA mutation could [receive] alpelisib [Piqray] plus targeted therapy. Patients who have mutations in the PI3K/AKT/mTOR pathway can qualify for treatment with capivasertib [Truqap], which is an AKT inhibitor. Based on the mutational analysis, they can qualify for 1 of these 3 therapies.
If the [patient does not display a] mutation, then you can administer endocrine therapy plus the mTOR inhibitor everolimus [Afinitor]. This is a targeted therapy that’s been almost forgotten, but it’s still available and is effective. mTOR inhibitors are used irrespective of a mutation in that pathway.
.
