Tumor biomarkers for diagnosis, prognosis and targeted therapy | Signal Transduction and Targeted Therapy
Thinking About Menopause Hormone Therapy? Start Here.
At Dr. Monica Christmas's clinic these days, she sees two kinds of menopausal patients. The first, she said, is suffering from the symptoms associated with this life phase, but is also wary of hormone therapy because she's heard there are health risks associated with it.
The second kind of patient is almost the exact opposite: she may not have symptoms at all, but nonetheless is asking for hormones because she's heard they will make her healthier.
"We seem to like these extremes," said Dr. Christmas, the director of the Menopause Program and Center for Women's Integrated Health at the University of Chicago.
Prescription data reflects a persistent anxiety around the health risks: In a study published in September, researchers found that only 5 percent of menopausal women used hormones in 2020 despite the fact that roughly 80 percent of women experience symptoms.
On the flip side, in the last few years, a growing number of social media influencers and celebrities, like Oprah Winfrey, have loudly endorsed hormone therapy, presenting it as a "magic elixir," Dr. Christmas said.
"Now there's this messaging that every woman who is menopausal should be on hormone therapy," she said. But women need more clarity around what hormone therapy can and can't do. "We've got to find our way back to the middle ground."
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Advancing Treatments For ET And CDK4/6 Resistance In HR+ Breast Cancer
New agents targeting endocrine therapy and CDK4/6 resistance in hormone receptor–positive breast cancer are in development.
Multiple novel agents with diverse mechanisms of action are currently in development to overcome resistance to endocrine therapy (ET) and CDK4/6 inhibitors in hormone receptor–positive breast cancer. This ongoing research, highlighted in a session by Hope S. Rugo, MD, at the 42nd Annual Miami Breast Cancer Conference, aims to address the significant unmet clinical need in this patient population.1
"We stand here at the brink of a precipice. There's going to be a whole lot of these drugs approved in the future. We're going to need to understand how to use them alone or in combination. They're oral agents, and that's huge for our patients," said Rugo, professor of medicine and Winterhof Professor of Breast Oncology, director, Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center. "I think that this is a really exciting advance. We've seen some great data in the past couple of years."
The first agents to kick off this sea change in managing resistant HR-positive breast cancer were the oral selective estrogen receptor degraders (SERDs), which work best in those with the ESR1resistance mutation. In 2023, the FDA approved the first of these agents, elacestrant (Orserdu), for patients with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following progression on at least 1 prior line of ET. This approval was based on data from the phase 3 EMERALD trial (NCT03778931).
In the phase 3 EMERALD trial,2 which enrolled patients with or without ESR1 mutations, the progression-free survival (PFS) was significantly prolonged with elacestrant compared with standard of care ET (HR, 0.70; 95% CI, 0.55-0.88; P = .002). In those with ESR1mutations, the benefit in PFS was even more pronounced with elacestrant compared with standard of care (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).
A follow up analysis further found that response to prior therapy could be used to help select which tumors would be more sensitive to treatment with elacestrant.3 For those who received ET plus CDK4/6 inhibition for 12 months or greater, the median PFS was 8.61 months (95% CI, 4.14-10.84) with elacestrant compared with 1.91 months (95% CI, 1.87-3.68) with standard of care (HR, 0.41; 95% CI, 0.26-0.63).
The ability to predict sensitivity led to the next question of whether combinations could be effective, Rugo noted. The ELECTRA (NCT05386108) and ELEVATE (NCT05563220) trials sought to examine this question by combining elacestrant with the CDK4/6 inhibitor abemaciclib (Verzenio). Data from a pooled analysis from the studies for patients pretreated with ET and CDK4/6 inhibitors were presented at the 2024 San Antonio Breast Cancer Symposium showing an intriguing efficacy.
In the analysis,4 the objective response rate (ORR) with the combination was 18%, which included 5% who had a complete response. There were 66% of patients beyond this who also had stable disease, for a clinical benefit rate (CBR) of 84%. In all patients, the median PFS with elacestrant plus abemaciclib was 8.7 months. In those who received prior ET/CDK4/6 treatment for 12 months or longer, the median PFS was 16.6 months with elacestrant plus abemaciclib.
Breast cancer, female anatomy: © peterschreiber.Media - stock.Adobe.Com
"We saw an encouraging clinical benefit rate," said Rugo. "Then we also looked at our response and many of these patients are staying on treatment for a long period of time, which is really encouraging."
Other SERDs on the HorizonOther investigational SERDs are also currently being explored as treatments for patients with ET and CDK4/6 resistance, potentially offering an abundance of choices soon. The phase 2 SERENA-2 trial (NCT04214288) was recently published showing efficacy for the SERD camizestrant vs fulvestrant (Faslodex) for patients with ER-positive, HER2-negative advanced breast cancer.5 The median PFS with fulvestrant was 3.7 months (90% CI, 2.0-6.0) compared with 7.2 months (90% CI, 3.7-10.9) with a 75-mg dose of camizestrant (HR, 0.59 vs fulvestrant) and 7.7 months (90% CI, 5.5-12.9) with a 150-mg dose (HR, 0.64 vs fulvestrant).
Recent data from the phase 3 SERENA-6 trial (NCT04964934) also showed utility for camizestrant in the first-line setting in combination with a CDK4/6 inhibitor.6 The data from the study have not yet been released but a statement said that the study met its primary end point of improved PFS with the combination compared with standard of care aromatase inhibition plus CDK4/6 inhibition. AstraZeneca, the company developing camizestrant, said the data would be presented at an upcoming medical meeting and shared with global regulatory authorities.
Another SERD, imlunestrant, has also demonstrated promise with or without the addition of abemaciclib for patients with ER-positive, HER2-negative advanced breast cancer in the phase 3 EMBER-3 trial (NCT04975308).7 In data from the study, the median PFS was 5.6 months (95% CI, 5.3-7.3) with imlunestrant and 5.5 months (95% CI, 4.6-5.6) with standard therapy (HR, 0.87; 95% CI, 0.72-1.04; P = .12); however, in those with ESR1 mutations, the median PFS was 5.5 months (95% CI, 3.9-7.4) with imlunestrant compared with 3.8 months (95% CI, 3.7-5.5) for standard therapy.
The combination of imlunestrant plus abemaciclib was also compared with imlunestrant monotherapy in the study. The median PFS with the combination was 9.4 months compared with 5.5 months with imlunestrant monotherapy (HR, 0.57; 95% CI, 0.44-0.73; P <.001). In those with ESR1 mutations, the median PFS with the combination was 11.1 months (95% CI, 7.4-13.7) compared with 5.5 months (95% CI, 3.8-7.2) with monotherapy (HR, 0.53; 95% CI, 0.35-0.80).
"The only downside here is that there's no comparison of imlunestrant/abemaciclib vs standard of care ET," said Rugo. "It is difficult to assess the impact of the ESR1 mutations in the combination group."
Another SERD, giredestrant, is also being examined in combination with palbociclib (Ibrance) plus letrozole in a phase 3 study labeled persevERA (NCT04546009).1 This trial is currently active but not recruiting, with an estimated primary completion date in October 2025.
Novel Agents for ER Targeting Under InvestigationThe novel agent vepdegestrant (ARV-471) offers another method for approaching ET resistance. The agent is a proteolysis-targeting chimera (PROTAC), which act as protein degraders targeted to ER proteins. A phase 1b study (NCT04072952) assessed vepdegestrant in combination with palbociclib for patients with ER-positive, HER2-negative breast cancer following exposure to ET with or without CDK4/6.8 The CBR with the combination was 63% (95% CI, 47.6%-76.8%) in the overall population enrolled. For those with the ESR1 mutation, the CBR was 72.4% (95% CI, 52.8%-87.3%). The median PFS was 11.2 months (95% CI, 8.2-16.5) in the overall population and 13.7 months (95% CI, 8.2-not reached) in the ESR1group.
In February 2024, vepdegestrant received a fast track designation from the FDA, a distinction that is meant to speed up the development of new medications. The phase 3 VERITAC-3 study (NCT05909397) is also assessing the agent with palbociclib compared with palbociclib and letrozole. The phase 3 VERITAC-2 trial (NCT05654623) is currently assessing vepdegestrant vs fulvestrant for patients with ER-positive, HER2-negative advanced breast cancer. The study indicates that it has fully recruited with results expected soon.
"These are very exciting drugs and many of them [are] still in development," said Rugo. "The trial is fully accrued so we're going to see the results relatively sooner."
Another approach to ET resistance comes through the complete ER antagonist (CERAN) palazestrant (OP-1250). This agent was examined in combination with ribociclib (Kisqali) in a phase 1b/2 study (NCT05508906). In findings from the study,9 the median PFS was not reached. The 6-month PFS rate was 72% across all patients and 81% in those with ESR1 mutations.
Based on these findings, Olema Oncology, the company developing palazestrant, is launching the phase 3 OPERA-02 study to further assess the combination for patients with breast cancer. The FDA granted palazestrant a fast track designation in 2022.
Disclosures: Rugo received institutional research support from AstraZeneca, Daiichi Sankyo, Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., Lilly, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer, Stemline Therapeutics, OBI Pharma, and Ambryx; and served in a consulting/advisory role for Chugai, Sanofi, Napo, and Mylan.
ReferencesNICE Approves Daily Pill For Endometriosis Where Other Treatments Have Failed
A daily pill has been approved by NICE for treating some women with endometriosis after initially being rejected.
It is estimated around 1,000 patients a year will be able to access the treatment called relugolix–estradiol–norethisterone (also known as relugolix combination therapy or Ryeqo).
The turnaround from NICE came after the company provided new evidence on the effectiveness and value for money of the treatment.
This included a broader systematic review of comparison treatments and long-term efficacy data collated by makers Gedeon Richter.
Clinical evidence shows that it reduces pain compared with placebo but it has not been directly compared in trials with usual treatment, the committee noted.
Indirect comparisons presented to NICE suggest that it is likely to reduce pelvic pain almost as well as GnRH agonists, but it is unclear it compares to surgery.
The ruling published as a final draft means the drug will be an option for treating symptoms of endometriosis in adults of reproductive age who have had medical – gonadotropin-releasing hormone (GnRH) agonists – or surgical treatment for the condition that has not worked.
It is the first long-term daily pill licensed to treat endometriosis symptoms and in eligible patients will eliminate the need for multiple medications and regular trips to clinics for injections, NICE said.
Committee members also agreed that compared with current injectable treatments, which can initially worsen symptoms, the daily pill starts working more quickly, combines all the hormones needed in one medicine and hormone levels return to normal more quickly when it is stopped.
A clinical expert advised the committee that the treatment would be 'a step-change in the management of endometriosis'.
Having an all-in-one daily tablet that includes hormone replacement therapy, also means the patient does not have to remember to take add-back therapy separately
Endometriosis affecting an estimated 1.5 million women in the UK. Updated guidelines on diagnosis and management of the condition were published by NICE in November.
Helen Knight, director of medicines evaluation at NICE, said: 'This new treatment marks a potential step-change in how we manage endometriosis, putting control back in patients' hands while ensuring value for the taxpayer.
'Instead of travelling to clinics for injections, there is now a daily tablet that can be taken at home. The treatment can also be stopped and started more easily, which is particularly important for those planning to have children and for managing side effects. This convenience not only benefits patients but reduces pressure on NHS services.'
A spokesperson for Endometriosis UK welcomed the decision saying women and those assigned female at birth in the UK should be able to choose the right treatment and management options for them.
'We recommend that treatment decisions are always made in partnership with the individual and their medical practitioner.
'There are far too few options available due to the historic lack of research into endometriosis.'
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