COMMENTARY

Clinical Advances in the Novel Endocrine Agent Treatment Paradigm: Past, Present, and Future

Erika P. Hamilton, MD; Komal Jhaveri, MD, FACP

Disclosures

October 07, 2022

This transcript has been edited for clarity.

Komal Jhaveri, MD, FACP: Welcome to today's two-part presentation, where Dr Erika Hamilton and I will be reviewing novel endocrine agents. I'm Komal Jhaveri, and I'm a breast medical oncologist at Memorial Sloan-Kettering Cancer Center in New York. I serve as a section head for the Endocrine Therapy Research Program, and I'm also the clinical director for our Early Drug Development Service.

Laying the Groundwork for Breakthroughs in Treatment

First, I will walk you through the success story of targeting the estrogen receptor pathway and discuss the rationale for developing novel endocrine agents and where we see them fit in our currently existing treatment paradigm. Dr Hamilton will then walk us through the clinical data for these various endocrine agents, including novel selective estrogen receptor degraders (SERDs), novel serum estrogen receptor modulators (SERMs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis-targeting chimeras (PROTACs), and complete ER-antagonists (CERANs).

The endocrine pathway, or the estrogen receptor, remains a critical target for patients whose tumors have estrogen dependence. The treatment landscape for hormone receptor–positive breast cancer patients has steadily evolved over the past century.

It was about 100 years ago when Sir George Beatson, for the very first time in 1896, described regression in chest wall nodules in a patient with metastatic breast cancer who had an oophorectomy. It took us about 100 years after that to get approval for the very first endocrine agent, tamoxifen, a SERM that inhibits the transcription of ER target genes that drive cellular proliferation.

Tamoxifen is a partial agonist of the estrogen receptor and works in both an agonistic and antagonist fashion in various different tissues. For example, it antagonizes the effects of estrogen in breast tissue. It was about the late 1990s when we had approval for our next class of agents, which was the aromatase inhibitors, which inhibit the conversion of androgen to estrogen in the body by inhibiting the enzyme aromatase. They've been approved for postmenopausal women and we've been utilizing them both in late- and early-stage ER-positive breast cancer.

Last but not least, we have approval for the SERD fulvestrant, which was originally approved in 2002 in the second-line metastatic setting after patients have progressed on prior aromatase inhibitors or prior endocrine therapy. It was not until 2010 when we learned the right dose to use for fulvestrant in clinic, which is 500-mg intramuscular injections in the buttocks every month.

Game-Changing Impacts on Standards of Care

It is very important to note that these advances were really game-changing for our patients and have changed our standard of care. However, they did not necessarily have a substantial efficacy improvement, meaning that when we looked at trials that led to the approval of aromatase inhibitors compared with tamoxifen, the hazard ratios were 0.8 and the efficacy gain was incremental.

However, the overall survival data were either immature or there was lack of significant overall survival benefit. I think this is something we really want to keep in mind as we now see data emerge for these newer endocrine novel agents, such as oral SERDs. We want to keep them in mind and provide context to this.

There are certainly challenges that we face with the currently approved agents, such as tamoxifen, aromatase inhibitors, and fulvestrant. These treatment challenges really arise from the limitations of these agents, which are not limited to the toxicity profile but include pharmacologic limitations.

What do I mean by that? We've seen emergence of ESR1 mutations. These are mutations that emerge under the selective pressure of aromatase inhibitors, especially in the metastatic setting, which can lead to progression of the tumors. In fact, 50% of patients with hormone receptor–positive breast cancer become resistant to these currently existing endocrine therapies, leading to therapeutic failure. However, many of these tumors do remain dependent on ER signaling.

What about with tamoxifen? We said tamoxifen is a partial agonist, and therefore it causes weaker ER suppression. That's why we think that there might be therapeutic failure to tamoxifen. With fulvestrant, we know that it's an intramuscular injection, so it lacks oral bioavailability, which might be appealing. Its efficacy is really dose dependent. We saw that the 500-mg dose was better than the 250-mg dose, but we cannot go any higher.

We have recent data where patients who progress on a CDK4/6 inhibitor, which is the current standard of care in the first- and second-line metastatic setting, have rather modest efficacy with single-agent fulvestrant, in the range of less than 2 months. Certainly, we need to do better.

We also have seen that among those tumors that acquire ESR1 mutations, not all ESR1 mutations respond to fulvestrant. For example, ESR1 Y537S does not necessarily respond well to fulvestrant. We certainly have all these challenges to overcome, which makes working on novel endocrine agents even more important.

When we think about these agents, aromatase inhibitors and tamoxifen are already approved in the adjuvant setting for early-stage disease. In early-stage disease, due to the toxicities of these agents, we see hot flashes, arthralgias, and myalgias. Patients really are not able to tolerate these, and the nonadherence rate can be really high. Certain studies have shown that about 50% of these patients are not able to complete the intended 5-year adjuvant endocrine therapy.

Because of that early discontinuation, there is a 45% increased risk for a disease-free survival event in the early stage. We certainly need to do better. Because of the work that has been done over the past decade to develop optimal endocrine agents that can overcome the current existing issues — the current toxicity issues, the current adherence issues, the current endocrine resistance mechanism issues, and the pharmacologic limitations — we have these exciting molecules, of which the oral SERDs are in furthest development.

Dr Hamilton will walk us through the clinical data for each of these classes, including oral SERDs and others, and go through all the data that we have now seen in the metastatic setting.

What has also become very exciting is that these oral SERDs have begun their journey for adjuvant therapy. There are large phase 3 trials evaluating these agents for early-stage disease with an attempt to improve outcomes. A few examples of those trials include the lidERA trial, which is a trial that is evaluating giredestrant upfront compared with aromatase inhibitors or tamoxifen. These are for patients with moderate- or high-risk ER-positive disease.

We also have trials such as AMEERA-6, which is evaluating amcenestrant, another oral SERD by Sanofi. In this trial, patients who had intolerance to aromatase inhibitors up to 30 months on their adjuvant journey — so anybody with 6-30 months of aromatase inhibitors but intolerant to those — would then be randomized to receive amcenestrant vs tamoxifen. Interestingly, even triple-positive patients (ER positive, HER2 positive) can be enrolled on the AMEERA-6 trial.

[Editor's note: An update on the AMEERA trial was published following the recording of this commentary: Press Release: Sanofi provides update on amcenestrant clinical development program.]

Then we have two other trials, the CAMBRIA-1 study with camizestrant and the EMBER-4 study with imlunestrant, which are evaluating the switch strategy, meaning that patients would be either on an aromatase inhibitor or tamoxifen for 2-5 years for early-stage adjuvant therapy, and those patients would then be eligible and get randomized to receiving the oral SERD vs continuing the current endocrine therapy.

[Editor's note: the CAMBRIA-1 study has not yet been added to ClinicalTrials.gov.]

The Goal of Optimal Efficacy Via the Optimal Therapeutic Index

Ultimately, the goal here in the metastatic setting and in the early-stage setting is to identify newer, novel endocrine agents that have the optimal therapeutic index and the optimal efficacy so that we can further improve outcomes for our patients.

In the metastatic setting, we'll see that these agents might have a role as a single agent that could be predominantly post-CDK4/6 inhibitor. A large amount of work is needed here to understand who that right patient would be that would derive the most benefit with just single-agent endocrine therapy, even though it's an optimal single-agent endocrine therapy. One such example, or a surrogate of such an example, is ESR1-mutant disease. If you have an ESR1 mutation, perhaps you will respond to these agents better, is what we have seen. Dr Hamilton will walk us through that.

We could see that these could be utilized with CDK4/6 inhibitors, but I think what we're now learning is that can we combine them with other approved agents. We know that alpelisib, a PI3K inhibitor, is approved for ER-positive breast cancer. Everolimus, an mTOR inhibitor, is approved for ER-positive breast cancer. The question is whether these oral SERDs or other novel endocrine agents become the preferred partners with alpelisib or everolimus in the metastatic setting post-CDK4/6 inhibition.

There is a large amount of exciting work and more to hear with respect to the data that Dr Hamilton will walk us through. Thank you.

Erika P. Hamilton, MD: Hello. I'm Dr Erika Hamilton, and I lead the Breast Cancer Research Program at Sarah Cannon Research Institute at Tennessee Oncology here in Nashville, Tennessee.

Today I'd like to discuss novel endocrine therapies with you. Certainly, we've had many advances in metastatic hormone receptor–positive breast cancer over the past decade. We have new targeted agents, certainly PI3 kinase inhibitors, CDK4/6 inhibitors that have taken this area by storm, and novel antibody-drug conjugates for later-line patients, with emerging data from ASCO 2022.

What we haven't had in the past two decades are novel endocrine agents. We're at a uniquely poised spot in time right now where we've had some positive data presented and some phase 1 trials of earlier agents across a variety of compounds that we know will be coming.

The Current Landscape of Existing Agents

First, let's talk about the agents that exist. We have SERDs, SERCAs, CERANs, PROTACs, and SERMs available in clinical trials right now. The most advanced of these really are the SERDs. You can think of this as a pill version, and it works in a similar way to fulvestrant.

What we've seen in the post-CDK4/6 landscape for our patients facing ER-positive breast cancer is that fulvestrant and single-agent endocrine therapy is just not performing the same as it used to. We have data from EMERALD that we'll talk about, as well as VERONICA, which really looked at fulvestrant with or without the addition of a medication called venetoclax; that was a negative trial. The progression-free survival of fulvestrant alone in patients who have already seen CDK4/6 inhibitors in the first line is less than 2 months, and obviously this is not good enough for our patients.

We think the novel oral SERDs are more active. They have the advantage of being active also in patients who have ESR1 mutations. Finally, they are oral, which is obviously very convenient for our patients not to be having intramuscular administrations of fulvestrant.

Eye-Opening Clinical Trial Outcomes

Our first trial that reported activity with SERDs was EMERALD. The EMERALD study was presented with elacestrant vs treatment of physician's choice endocrine therapy, which included aromatase inhibitors and fulvestrant as options. This was a positive trial. It improved progression-free survival from 1.9 months up to 2.8 and was statistically significant.

To be quite honest, I think we were all a little bit disappointed in the magnitude of benefit. When we really dove in and looked at this trial, it looked like there was a good number of patients who didn't derive benefit from either arm, from endocrine therapy in general. What we're learning is that some patients post-AI and -CDK4/6 are really endocrine resistant at that point and probably are not appropriate for further endocrine therapy, but we haven't gotten quite sophisticated enough to be able to pick out who those patients may be.

If we also look at the EMERALD trial, if we select for those patients with ESR1 mutations, our magnitude of benefit is improved. It's larger, so it went from 1.9 months, again, with fulvestrant or the endocrine agents in the standard-of-care arm up to 3.8 months with elacestrant. Certainly, by picking out patients who have ESR1 mutations, we may be selecting patients who are more driven by estrogen, so driven by estrogen that they have this ESR1 mutation that's emerged, and a way to select patients who may have greater benefit.

We have seen two press releases from two other oral SERDs but, unfortunately, we hear that their trials are negative. It really remains to be determined why that may be — whether this was patient selection; difference in the drugs; the way the trial was designed or powered; the size of the trial — as we've not seen the full presentations for those yet.

We also saw a unique trial called PADA-1 recently that looked at patients who were receiving first-line aromatase inhibitors in combination with palbociclib. They followed them serially for emergence of an ESR1 mutation. If an ESR1 mutation emerged for a patient while they were on a first-line aromatase inhibitor and CDK4/6 inhibitor, they were randomized either to get an aromatase inhibitor and CDK4/6 inhibitor or switch to be getting fulvestrant with palbociclib, so switching the endocrine backbone.

Again, these were for patients who only had ESR1 mutations that were popping up but who had not had any signs of actual clinical progression yet. What we saw as part of that trial was that there was benefit for switching to fulvestrant-palbociclib. Those patients had a progression-free survival of over 11 months, whereas for those who remained on aromatase inhibitors with palbociclib, it was only 5.7 months.

Looking Ahead

Now, the big question that I have moving forward is that because those patients will still go on to get fulvestrant, what does the progression-free survival  look like? In other words, are we just using our therapies earlier or are people doing better long term with the so-called early switch strategy?

In fact, there's a trial enrolling right now called SERENA-6, which is looking at first-line monitoring for ESR1 mutations and randomizing patients either to stay on aromatase inhibitor in combination with CDK4/6 or switching to receive an oral SERD in combination with CDK4/6, so really looking at whether SERDs may have a place in early switch strategies.

I think the most eminent place that we're probably going to see SERDs is in that second-line space post–aromatase inhibitor and CDK4/6, but there are certainly trials like SERENA-6 for an early switch, trials in the first-line setting comparing SERD and CDK4/6 vs aromatase inhibitor and CDK4/6, or even adjuvant trials.

Fulvestrant actually beat aromatase inhibitors in the adjuvant setting, but by the time we figured out the exact dosing of fulvestrant and that we really need to be giving 500 mg instead of 250 mg, patent life was out and the large registrational trial was never done. Otherwise, I think we would probably all be using fulvestrant in the adjuvant setting instead of aromatase inhibitors.

Briefly, I'd also like to talk about some of what I call SERD cousins, so not SERDs, but also endocrine agents that work in a different fashion. We have PROTAC, and this is a proteolysis-targeting chimera. It's essentially a unique molecule that binds the estrogen receptor and then recruits E3 ligase.

When it recruits the E3 ligase, it ubiquitinates the estrogen receptor, which is a fancy way intracellularly to flag the estrogen receptor for destruction. When this happens, the PROTAC essentially enables the cell to recognize the estrogen receptor, chew it up, and spit it out. That's how I explain it to patients.

We've seen data from ARV-471. This was a phase 1 trial of heavily pretreated patients who had a median of four priors, all had seen CDK4/6 inhibitor, and over 80% had seen a SERD, whether that was fulvestrant or an oral SERD. Our clinical benefit rate here was 40%. They have expansions with ARV-471, and they also have expansions in combination with palbociclib, so I think that's a compound that we'll hear more about.

Additionally, we've seen recent data at ASCO for a SERM. We have a compound, an oldie but goodie — tamoxifen — which also fits in this category. Lasofoxifene was initially developed for vulvar vaginal atrophy and they noted that it had prevention and treatment of breast cancer characteristics.

ELAINE 2 was a single-arm trial looking at lasofoxifene in combination with abemaciclib for patients who had already seen a CDK inhibitor and an aromatase inhibitor, so essentially second line. Of the patients, 97% had already seen a CDK4/6 inhibitor and about half had already been on chemotherapy.

The progression-free survival here was 13 months, which I really think was very impressive to many of us. The overall response rate was 50%. Being a single-arm trial, we can't fully tease out the benefit of switching aromatase inhibitor from one to abemaciclib or switching endocrine backbone to lasofoxifene. Certainly, the combination of lasofoxifene with abemaciclib was quite exciting. They have other trials underway as well.

An additional endocrine therapy is the SERCA. It irreversibly binds without degrading the estrogen receptor, so it just causes an antagonistic conformational change.

In the phase 1 trial, again, this was a heavily pretreated population with a median of about three priors. Almost 90% of patients had seen a CDK4/6 inhibitor, about three quarters had seen fulvestrant, and there was a very similar clinical benefit rate here of about 40%. Progression-free survival was just shy of about 4 months. Again, if we select for patients who had clonal ESR1 mutations as a mechanism of resistance to previous endocrine therapies, our progression-free survival was lengthened to 7.3 months. Certainly, we're going to be seeing more with that compound as well.

Finally, I'd like to talk about a CERAN. This turns off both AF-1 and AF-2 within the estrogen receptor, so both activation functions instead of just one, which is where most endocrine agents act. Similarly, the phase 1 study included patients who were heavily pretreated, where 50% of patients had seen at least three prior lines of therapy, almost universal CDK4/6 inhibitor, about 70% of patients having received prior fulvestrant. The clinical benefit rate, again, was quite similar at 38%.

The Way Forward

Where do we go from here? I think in the coming years, we're probably going to have new endocrine agents for ER-positive breast cancer for the first time in decades, which is certainly very exciting, being able to now combine our targeted agents with a new endocrine backbone. I think we're all recognizing that fulvestrant and single-agent endocrine therapy is not performing as well as we want it to for our patients, who almost universally now are post–aromatase inhibitor and -CDK4/6.

Probably first to the stage will be our oral SERDs. Again, there are many places where these agents may end up, such as second line after aromatase inhibitor and CDK4/6, in combination with CDK4/6 and replacing aromatase inhibitors for metastatic disease, in an early switch strategy, and they may end up in the adjuvant setting as well, with trials ongoing.

Thank you so much for joining.

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