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, 

-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; 

 Updated findings from the study presented at the 

 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).

, 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.

: 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?

: 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—

—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 

 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 

 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 

 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] 

 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]?

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.

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. 

. 2024;42 (suppl 16):1003. Doi: 10.1200/JCO.2024.42.16_suppl.1003.

Articles

Seth Wander, MD, PhD on novel anti-estrogen therapies that could expand treatment options in estrogen receptor–positive advanced breast cancer.

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

Dr Wander on Limitations of First- and Later-Line Therapies in HR+ Breast Cancer

Seth Wander, MD, PhD, instructor, medicine, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses the present limitations of first- and later-line therapy for patients with hormone receptor (HR)–positive metastatic breast cancer.

In recent years, significant progress has been made in the development of novel frontline therapies for patients with HR-positive metastatic breast cancer, Wanderbegins. The current standard of care often includes an aromatase inhibitor combined with a CDK4/6 inhibitor, such as ribociclib (Kisqali), a regimen that has generated astatistically significant improvement in overall survival in the first-line setting, he explains.

However, there are still limitations and areas for improvement in treatment, Wandernotes. He says that on one end of the spectrum, patients with more aggressive disease—particularly those who progress shortly after adjuvant anti-estrogen or CDK4/6 inhibitor therapy—represent a high-risk population that requires more effective treatmentstrategies. Recent data from the phase 2/3 INAVO120 trial (NCT04191499) have shown that patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer harboring 

 mutations who have progressed on adjuvant anti-estrogen therapy benefit from a triplet regimen of fulvestrant (Faslodex), palbociclib (Ibrance), and the novel PI3K inhibitor inavolisib (GDC-0077). The positive findings seen in this trial highlight the possibility of developing more effective treatment approaches for these endocrine-refractory patients, he continues.

Conversely, there is a subset of patients with slower-growing, indolent disease—such as those with oligometastatic or bone-only HR-positive breast cancer—for whom CDK4/6 inhibitors may not be suitable due to their associated financial burdens, toxicities, and adverse effects, Wander adds. These patients could achieve sufficient disease control with anti-estrogen therapy alone, which highlights the need for a more tailored approach to therapy for this population, he expands.

A key unmet need in this population is identifying which patients can be effectively treated with endocrine therapy alone and which require more aggressive, upfront therapy, potentially including triplet-targeted agents, Wander states. Additionally, advancing biomarker development will be critical for optimizing treatment strategies and personalizing care across this diverse patient population, Wander concludes.

Videos

Seth Wander, MD, PhD, discusses the present limitations of first- and later-line therapy for HR+ metastatic breast cancer.

Although treatment with CDK4/6 inhibitors have bolstered the treatment paradigm for estrogen receptor (ER)–positive metastatic breast cancer, novel classes of agents could add therapy options for patients who develop resistance and experience disease progression, according to Komal Jhaveri, MD, FACP.

Oral selective estrogen receptor degraders (SERDs) have already entered the space after 

elacestrant (Orserdu) was approved by the FDA

 in January 2023 for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.

Another novel class of agents known as proteolysis targeting chimeras (PROTACs) could be the next to alter the treatment paradigm. Vepdegestrant (ARV-471) is currently under investigation in the phase 3 VERITAC-2 study (NCT05654623), which is evaluating the oral PROTAC as monotherapy vs fulvestrant (Faslodex) alone in patients with previously treatment ER-positive, HER2-negative advanced breast cancer.

“We have to think about how we use agents that may be available, and more importantly, focus on mechanisms of resistance [of different classes of] agents and how to optimally sequence them with various combinations to further improve outcomes for our patients [with advanced ER-positive breast cancer],” Jhaveri explained in an interview with 

®. “A lot more still needs to be done, but these are exciting times. We are looking forward to more data to understand this better.”

In the interview, Jhaveri discussed the gamut of emerging treatment options and strategies in ER-positive metastatic breast cancer. She highlighted current limitations of frontline treatment; the development of oral SERDs and PROTACs, noting key differences between these 2 classes; and treatment approaches for patients without targetable mutations following disease progression on a CDK4/6 inhibitor.

Jhaveri serves as the section head of Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

: What current limitations exist within the frontline treatment setting for patients with ER-positive metastatic breast cancer?

: First-line therapy has been an unprecedented game changer for our patients with the addition of CDK4/6 inhibitors to endocrine therapy, and [data for these agents] have now read out to [show an] overall survival [OS] benefit. In fact, with ribociclib [Kisqali], we saw a median OS more than 5 years [in the phase 3 MONALEESA-2 trial (NCT01958021) when combined with endocrine therapy], regardless of menopausal status.

[The addition of CDK4/6 inhibitors to endocrine therapy] has been revolutionizing in terms of how we treat our patients in the first line. Despite this [progress], there is a proportion of patients who either have primary endocrine resistance or develop acquired resistance to [CDK4/6 inhibitors], which is why the tumors continue to grow. 

We want to figure out how to treat these patients effectively once the tumors have progressed on first-line therapy, and that's been our big focus in terms of figuring out the optimal way of sequencing therapies following progression on CDK4/6 inhibitors.

What has been seen in the investigational landscape for patients who experience disease progression on CDK4/6 inhibitors? How do endocrine therapies fold into this equation?

A lot of research is either ongoing or has been conducted. The one thing that has become successful in the clinic is trying to understand the genomic landscape for patients. [This means] not only understanding if patients have any germline 

 mutations, where we could utilize PARP inhibitors, but also understanding the [greater] tumor genomic landscape. How could that be contributing to tumor growth?

In that context, the oral SERD elacestrant [Orserdu] was approved [by the FDA] for those tumors that harbor 

 mutations. For patients with tumors that harbor either a 

we recently had an approval for the AKT inhibitor capivasertib [Truqap] in combination with fulvestrant

approval of the PI3K inhibitor alpelisib [Piqray]

 in combination with fulvestrant for those patients with tumors that harbor 

This is [what we] think about in clinic when a patient's tumor progresses. How do we assign the best next treatment option? We consider a few of these factors, including biomarker testing, to figure out the right way of approaching [treatment for] a patient in clinic.

How do you approach the treatment of patients with an absence of any of the actionable mutations with approved targeted therapies?

For patients who do not have an actionable mutation, we do 

have FDA approval for everolimus [Afinitor].

That approval predates the data for CDK4/6 inhibitors. We have real-world data sets and some smaller data sets for CDK4/6 inhibitors [after progression on a prior CDK4/6 inhibitor]. We have data for everolimus in combination with exemestane—

—from the phase 3 BOLERO-2 trial [NCT00863655]. We also have some data with other endocrine agents, including fulvestrant and tamoxifen.

Clinical trials are relevant in this context because there are a lot of novel endocrine agents that are now being studied in combination with various targeted agents, including agents targeting the PI3K, AKT, and mTOR pathways, as well as CDK4/6 inhibitors. Later [in 2024], we also hope to see data from the phase 3 EMBER-3 trial [NCT04975308], which evaluated the oral SERD imlunestrant [LY3484356] compared with standard-of-care endocrine therapy; we will also evaluate data for imlunestrant in combination with abemaciclib [Verzenio] in the same trial. Therefore, we [will] have another dataset for a CDK4/6 inhibitor [after progression on a] CDK4/6 inhibitor, but these will be the first data [for a CDK4/6 inhibitor after progression] in combination with a novel endocrine agent—in this case, an oral SERD.

Talking about the role of CDK4/6 inhibitors beyond CDK4/6 inhibitors as a potential treatment strategy, we have data now from 

the phase 3 postMONARCH trial [NCT05169567] that was presented by Kevin Kalinsky, MD, MS

, of Winship Cancer Institute of Emory University in Atlanta, Georgia, at the 

. We saw modest improvement in median progression-free survival favoring the combination compared with fulvestrant alone. That difference in benefit seemed to be rather modest; however, the hazard ratio seemed like it was effective and statistically significant.

What was interesting in the subgroup analysis, which was also shown by Kalinsky, was that the combination was effective regardless of 

 mutation status. For some patients, potentially, that strategy may also be considered, and it could be an attractive strategy for patients without those mutations. When we're thinking about patients without actionable mutations, we're thinking about the reintroduction of a CDK4/6 inhibitor with endocrine therapy and switching the endocrine backbone. In this case, it was fulvestrant.

In terms of elacestrant, where has that agent fallen short, and how could some of these novel combinations help fill that gap?

We have good monotherapy data that led to the approval [in patients with] tumors that harbor 

 mutations. There were some interesting analyses that were presented and published earlier [in 2024] in 

 by Aditya Bardia, MD, MPH, FASCO, of the University of California, Los Angeles, and colleagues, where they focused on evaluating patients with tumors that harbored 

 mutations who had a durable benefit on a CDK4/6 inhibitor prior to receiving elacestrant. We learned that, potentially, in patients who had a durable benefit on a CDK4/6 inhibitor and harbored an 

 mutation, it may be appropriate for a single-agent oral SERD—in this case, elacestrant.

The ongoing phase 1b ELEVATE trial [NCT05563220] is evaluating various combinations of elacestrant with other targeted agents, including other CDK4/6 inhibitors and agents targeting the PI3K, AKT, and MTOR pathways. We also have [the phase 1b/2 ELECTRA trial (NCT05386108)] evaluating the role of elacestrant [in combination with abemaciclib] in patients with brain metastases, which is not as common early in the disease course for patients with ER-positive breast cancer, unlike patients with triple-negative breast cancer or HER2-positive breast cancer.

Those attempts of trying to understand elacestrant’s role in these patient populations are important and relevant. We are hoping to see additional data sets coming out for combinations, and then hopefully some larger studies will further establish the role of these elacestrant-based combinations.

Other oral SERDs are also in late-phase development. We have the phase 3 evERA trial [NCT05306340], which is evaluating giredestrant [GDC-9545] in combination with everolimus compared with endocrine therapy plus everolimus. That study is currently ongoing.

The phase 3 pionERA trial [NCT06065748] is evaluating giredestrant plus fulvestrant and a CDK4/6 inhibitor compared with a standard-of-care fulvestrant plus a CDK4/6 inhibitor.

[Oral SERDs such as elacestrant] are effective compared with standard-of-care endocrine therapy, especially in [patients with] 

-mutant tumors as monotherapy. Perhaps for a larger group of patients, combinations [with oral SERDs] are relevant, and these combinations might establish the role of novel endocrine agents as the backbone-preferred partner once we have some readouts from larger studies. [We are] looking forward to that and hoping that we can further impact the outcomes for our patients with these combinations.

How are PROTACs mechanistically different from SERDs?

[In the ER-positive breast cancer space], we have novel selective estrogen receptor modulators [SERMs], oral SERDs, PROTACs, and complete estrogen receptor antagonists [CERANs]. What we are trying to achieve with all these agents is one common, ultimate goal: identifying novel endocrine therapies that can overcome the toxicities that patients face with tamoxifen, aromatase inhibitors, and fulvestrant. For instance, oral SERDs can overcome the issue of 

 mutations that fulvestrant might not potentially be able to overcome. The efficacy with fulvestrant following CDK4/6 inhibitors has not been super promising. Oral SERDs [could represent an improvement] over endocrine therapy, and elacestrant has shown that.

Similarly, PROTACs are [being investigated in a similar fashion]. We're trying to see if these agents have an optimal therapeutic window, if they have optimal therapeutic efficacy, and how they differ in their toxicity profiles. The goal is to have down regulation of the ER and overcome any pharmacologic limitations and resistance mechanisms, such as 

 mutations. However, we must also establish the best therapeutic window, therapeutic efficacy, and safety profile.

PROTACs are slightly mechanistically different [from oral SERDs] in that they have a different way of achieving ER degradation and down regulation. Larger studies [with PROTACs] are already ongoing. This includes the first PROTAC vepdegestrant [ARV-471], and we're looking forward to trials such as the phase 3 VERITAC-2 study [NCT05654623], which is comparing vepdegestrant monotherapy vs fulvestrant monotherapy.

Additional phase 1 trials [are investigating vepdegestrant] in combination with other agents [with the goal of understanding] if, in clinic, that difference in mechanistically down regulating the ER will translate into a benefit and show that PROTACs may be a better way to approach [treatment]. However, we are never going to have head-to-head trials. We're not going to have a head-to-head trial comparing a PROTAC with an oral SERD. Will we be able to definitively address whether a PROTAC is better than any other agent? Maybe not; however, depending on the efficacy signal and safety profile, we may be able to learn something about this. 

FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed September 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer

A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer (VERITAC-2). ClinicalTrials.gov. Updated August 2, 2024. Accessed September 11, 2024. https://clinicaltrials.gov/study/NCT05654623

Komal Jhaveri, MD, FACP, discusses the emergence of oral SERDs and PROTACs in the treatment of estrogen receptor–positive advanced breast cancer.

Oral SERDs, PROTACs Could Add to Expanding ER+ Advanced Breast Cancer Arsenal

Dr Jhaveri on the Use of CDK4/6 Inhibitors Plus Endocrine Therapy in Breast Cancer

Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center, discusses the current state of the frontline treatment paradigm, as well as ongoing developments, for patients with estrogen receptor (ER)–positive metastatic breast cancer.

First-line therapeutic approaches have transformed over the years for patients with ER-positive metastatic breast cancer in large part because of the incorporation of CDK4/6 inhibitors alongside endocrine therapy, Jhaveri begins. These treatments have demonstrated a significant overall survival benefit, she explains, adding that with ribociclib (Kisqali), survival rates have exceeded 5 years, irrespective of menopausal status, marking a revolution in patient treatment. However, a subset of patients either exhibit primary endocrine resistance or develop acquired resistance to these agents, which results in continued tumor growth, according to Jhaveri. This underscores the need to determine effective treatment strategies for patients whose tumors progress after first-line therapy, Jhaveri emphasizes.

Investigators’ primary focus has been on identifying the optimal sequence of therapies following disease progression on CDK4/6 inhibitors, she continues. Substantial research has been conducted, and ongoing trials aim to address these challenges, she notes. Breakthroughs have resulted from a deeper understanding of the genomic landscape in patients with resistant disease, Jhaveri states. This involves identifying germline 

 mutations and investigating other genomic alterations that could guide treatment decisions, such as utilizing PARP inhibitors to target specific genetic profiles, she says.

Recent FDA approvals reflect these advancements, Jhaveri explains. For example, the oral selective estrogen receptor degrader 

approved for patients with ER-positive, HER2-negative advanced or metastatic breast cancer harboring

, Jhaveri expands. Additionally, in November 2023, the AKT inhibitor 

capivasertib (Truqap), in combination with fulvestrant (Faslodex), received FDA approval

 for patients with hormone receptor (HR)–positive, HER2-negative breast cancer harboring 

 mutations. Moreover, alpelisib (Piqray) is now used in combination with fulvestrant for patients with HR-positive, HER2-negative breast cancer with 

Currently, clinical decisions are increasingly informed by biomarker testing, enabling more personalized treatment strategies, Jhaveri emphasizes. This approach ensures that subsequent therapies are tailored to the molecular characteristics of the tumor, optimizing patient outcomes, she concludes.

Exacting the Role of Novel Endocrine Therapies in ER+ Metastatic Breast Cancer | Supplements and Featured Publications

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

Dr Wander on Limitations of First- and Later-Line Therapies in HR+ Breast Cancer

Oral SERDs, PROTACs Could Add to Expanding ER+ Advanced Breast Cancer Arsenal

Dr Jhaveri on the Use of CDK4/6 Inhibitors Plus Endocrine Therapy in Breast Cancer