Novel Hormone Strategies Gain Ground in Breast Cancer

Hope Rugo, MD

Although hormone-targeting therapies have been a long-established strategy for the treatment of estrogen receptor (ER)-positive breast cancer, more than 20% of patients with early-stage disease relapse and those who progress to a metastatic stage eventually die from their illness.¹

Research efforts to identify mechanisms of resistance to therapy and develop novel agents and combinations to attack those networks are producing tangible results that have translated into fresh options in clinical practice. The FDA has approved several new agents for this patient population in recent months and expanded the indications of previously approved drugs.

Resistance to endocrine therapy in patients with ER-positive breast cancer is defined in 2 ways 2 :

• Primary resistance: recurrence within adjuvant therapy or disease progression less than 6 months after treatment
• Acquired resistance: recurrence at least 12 months after completion of adjuvant therapy or progression 6 months or more after the initiation of endocrine therapy in the metastatic setting

Several key mechanisms of endocrine resistance have been identified, including the PI3K/AKT/ mTOR growth factor signaling network, cyclindependent kinase (CDK) signaling, and histone deacetylase (HDAC) activity. Strategies aimed at these processes have been among the most active attempts to boost the efficacy of endocrine therapies (Figure).^1,2

Figure. Targeting Endocrine Therapy Resistance

Ingrid A. Mayer, MD, MSCI, co-leader and clinical director of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center, distinguished between mechanisms of primary and acquired resistance during a presentation at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in June.²

For example, primary resistance may be driven by CDK amplification or expression while activation of growth factor signaling and mutations in the ER pathway are associated with acquired resistance.₂ Mutations in the ESR1 gene, which encodes ER-alpha, have been reported in 11% to 55% of recurrent or metastatic cancers that have progressed after long-term endocrine therapy, Hope S. Rugo, MD, and colleagues noted.¹

“The development of ESR1 mutation following endocrine therapy provides further evidence that ER remains relevant in resistant tumors. Combination strategies that target both ER and resistant pathways are therefore rational approaches to overcome endocrine resistance,” the authors wrote. They said that cost and toxicity would increase with the addition of targeted therapies.

In her ASCO presentation, Mayer stressed the need for new approaches to circumvent resistance by preventing progression and more effectively treating metastatic disease. She noted that some new therapies have been effective at delaying disease progression but that “people still die of metastatic disease.”

CDK4/6 Inhibitors

“We have very effective therapies for ER-positive metastatic breast cancer, there’s no question about that,” Mayer said. “But we don’t know yet if these therapies are needed at all times. A lot of the ongoing trials are trying to answer whether we are going to sequence or combine all these approved or to-beapproved targeted [therapies] in everybody and what is going to be the cost of that not just financially but obviously from a side effect and tolerance point of view. My answer to that is, we don’t know yet.”The development of CDK4/6 inhibitors has been an area of rapid growth in the breast cancer field in the past several years and 3 agents are now approved that employ this approach: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).

In February 2015, palbociclib became the first agent in this class to gain the FDA’s approval in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with hormone receptor—positive (ER- plus progesterone receptor–positive), HER2-negative advanced breast cancer The approval was based on findings from the phase II PALOMA-1 trial in which the palbociclib-containing regimen doubled progression-free survival (PFS) compared with letrozole alone: 20.2 versus 10.2 months (HR, 0.488; 95% CI 0.32–0.75; P = .0004). Palbociclib has since been approved in combination with fulvestrant (Faslodex) in women with hormone receptor—positive, HER2-negative advanced or metastatic breast cancer following progression on endocrine therapy. In March, palbociclib gained a broader approval in combination with an aromatase inhibitor (AI) as first-line therapy for postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic disease. This indication is based on findings from the phase III PALOMA-2 trial in which palbociclib plus letrozole resulted in a median PFS of 24.8 months versus 14.5 months in the placebo-plus-letrozole arm (HR, 0.576; 95% CI, 0.463- 0.718; P <.0001).³ Overall survival (OS) data were not yet mature.

Also in March, the FDA approved ribociclib in combination with an AI as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor—positive, HER2- negative advanced or metastatic breast cancer. Updated results from the pivotal phase III MONALEESA-2 trial presented at the 2017 ASCO Annual Meeting indicated that ribociclib plus letrozole improved median PFS in the frontline setting to 25.3 months compared with 16.0 months with letrozole plus placebo (HR, 0.568; 95% CI, 0.457- 0.704; P <.001).⁴

In September, abemaciclib was approved as monotherapy for women with metastatic hormone receptor—positive, HER2-negative breast cancer who have previously received endocrine therapy and chemotherapy and in combination with fulvestrant in patients with advanced disease following progression on endocrine therapy.

Support for the combination indication comes from the phase III MONARCH 2 trial, in which adding abemaciclib to fulvestrant reduced the risk of disease progression or death by 45% versus fulvestrant alone. The single-agent approval was based on the phase II MONARCH 1 trial, in which the median PFS in this patient population was 6 months (95% CI 4.2-7.5) and the median OS was 17.7 months (95% CI, 16 to not reached).

Less than 1 month later, the FDA granted a priority review for the use of abemaciclib in combination with an AI for the frontline treatment of women with hormone receptor—positive, HER2-negative advanced or metastatic breast cancer. The application was based on data from the phase III MONARCH 3 trial in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with a nonsteroidal AI alone for previously untreated patients.5

In the phase III study, the median PFS was not yet reached in the abemaciclib arm versus 14.7 months with the AI alone (HR, 0.543; 95% CI, 0.409-0.723; P = .000021). In those with measurable disease, the objective response rate (ORR) was 59.2% with abemaciclib and 43.8% in the control arm (P = .004). Although the 3 approved drugs target CDK signaling, which controls the G1 to S phase transition in the cell cycle, there are differences in their mechanisms of action. Palbociclib and ribociclib inhibit CDK4/6, while abemaciclib more potently inhibits CDK4.¹

The most common toxicity from abemaciclib is diarrhea while the primary adverse event with palbociclib and ribociclib is neutropenia. The impact of these agents on the treatment of patients with breast cancer has been significant.

“We’ve seen a real revolution in the treatment paradigm for patients with hormone receptor—positive metastatic breast cancer, where CDK4/6 inhibitors have really impacted our treatment planning and our guidelines as well. In fact, the use of CDK4/6 inhibitors has been incorporated into guidelines, nationally and internationally,” said Rugo, a clinical professor of medicine and director of the Breast Clinical Trials Program at the UCSF Helen Diller Family Comprehensive Cancer Center, during an OncLive^® Insights program.⁶

Targeting the PI3K Pathway

“The impact in terms of the treatment paradigm is that now when you have a patient who has hormone receptor—positive metastatic breast cancer, the decision is, ‘I’m going to give hormone therapy. Should I also give a CDK4/6 inhibitor?’ And in most cases, that answer is yes in the first-line or subsequent line setting, depending on the individual patient setting and situation and the organs that are involved,” she said.Dual targeting strategies for patients with hormone receptor—positive, HER2-negative breast cancer received a boost in 2012 with the approval of everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin (mTOR) kinase downstream of the PI3K/AKT pathway. The FDA approved everolimus for the treatment of postmenopausal women with advanced hormone receptor– positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

The approval stemmed from the BOLERO-2 trial in which the median investigator-assessed PFS was 7.8 months with everolimus plus exemestane compared with 3.2 months with placebo plus exemestane (HR, 0.45; 95% CI, 0.38-0.54; P <.0001). Toxicity is a substantial issue with everolimus, although physician and patient education and “expectant management” can alleviate problems.1 The most common toxicity in the BOLERO-2 trial was stomatitis (56%, all grade); other adverse effects included fatigue, diarrhea, rash, hyperglycemia, pneumonitis, weight loss, anemia, and thrombocytopenia.¹

Novel agents that target the PI3K pathway more directly are under investigation. In September, results were reported for taselisib, a selective PI3K inhibitor, in postmenopausal women with ER-positive, HER2-negative early breast cancer.

In the phase II LORELEI study, the addition of taselisib to standard letrozole therapy demonstrated a 50% ORR among women with operable stages I to III breast cancer versus 39.3% for patients who received letrozole plus a placebo (OR, 1.55; 95% CI,1.00-2.38; P = .049).7 The trial enrolled 334 patients with and without PIK3CA mutations. Patients with mutations derived a greater benefit from taselisib than those without mutations (OR, 2.03; 95% CI, 1.06-3.88; P = .033).

HDAC Inhibitors

Taselisib differs from other PI3K inhibitors since it degrades mutated p110 alpha by a unique mechanism of action and provides enhanced activity against PIK3CA-mutant cancer cells. “LORELEI is the first randomized study to demonstrate a significant increase in objective response rate upon treatment with a PI3K selective inhibitor in this population of patients,” said Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology in Barcelona, Spain. She presented the data at the 2017 European Society for Medical Oncology Conference in September.Another avenue of attack against hormonedriven breast cancers focuses on epigenetic processes, such as activity promoted by HDACs. Entinostat, an HDAC inhibitor, is under investigation in the phase III E2112 trial in combination with exemestane versus exemestane plus placebo. The study seeks to randomize 600 patients with stage III locally advanced or metastatic, hormone receptor—positive, HER2-negative breast cancer.

The combination has generated excitement in the oncology drug development field after demonstrating an OS benefit of 28.1 months versus 19.8 months with exemestane and placebo (HR, 0.59; 95% CI, 0.36-0.97; P = .036) in an exploratory endpoint of a phase II trial.⁸ Those positive results prompted the FDA to grant a breakthrough therapy designation to entinostat in this setting.

Fulvestrant Advances

“This overall survival benefit is something that we don’t see very frequently and, in fact, has not been seen to date with any other combinations that are currently approved in this space,” said Roisin M. Connolly, MB BCh, principal investigator for the E2112 trial, in an interview with OncologyLive^®. “Recent combinations of agents have indicated a progression-free survival advantage— some very significant&mdash;and have led to FDA approval, but none of them have yet shown an overall survival advantage, so we’re very excited about running this phase III study, and we hope that it will confirm the results,” said Connolly, who is an assistant professor of oncology at Johns Hopkins Medicine in Baltimore.Although efforts to improve the effectiveness of endocrine therapy through combinations make up a robust area of research, investigators also have explored ways of better utilizing established hormone-targeting agents.

In August, the FDA approved fulvestrant for use as monotherapy in hormone receptor—positive, HER2-negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy. The synthetic ER antagonist has been approved in the United States since 2002 for the treatment of hormone receptor–positive, metastatic breast cancer in postmenopausal women with disease progression after endocrine therapy; last year it was approved in combination with palbociclib as second-line therapy in this patient population.

The frontline approval was based on results from the phase III FALCON trial, which showed that fulvestrant extended median PFS by 2.8 months compared with anastrozole (16.6 vs 13.8 months; HR, 0.80; 95% CI, 0.637- 0.999; P = .049).⁹

Immunotherapy

“This study provides evidence that using fulvestrant as the first option for previously untreated hormone receptor—positive advanced breast cancer will prolong the time before the disease advances and alternative therapies are required,” Matthew J. Ellis, MD, PhD, director of the Lester and Sue Smith Breast Center, part of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, said in a statement.As with many other areas of oncology research, combination therapies involving PD-1/PD-L1 pathway inhibitors are being explored for patients with ER-positive, HER2-negative breast cancers. Thus far, monotherapy with immune checkpoint blockade therapies has not been promising for these patients. The ORR was in the 6% and 12% in 2 recent clinical trials evaluating this class of agents in patients with metastatic disease, according to Mayer.²

Mayer said research has shown that ER-positive metastatic breast tumors resistant to endocrine therapy have an increase in mutational burden—a factor that has suggested better outcomes in other tumor types&mdash;but that in this case these tumors are “generally immunologically ‘cold.’”

“Immunotherapy combination strategies that increase immune recognition through enhanced antigen presentation and/or increase T-cell homing may increase immunotherapy response,” she said.

References

1. Rugo HS, Vidula N, Ma C. Improving response to hormone therapy in breast cancer: new targets, new therapeutic options. Am Soc Clin Oncol Educ Book. 2016;35:e40-54. doi: 10.14694/EDBK_159198.
2. Mayer IA. Future directions in overcoming endocrine resistance. Presented at: 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. meetinglibrary.asco.org/ record/138129/video. Accessed October 22, 2107.
3. Palbociclib (Ibrance). FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549978.htm. Updated March 31, 2017. Accessed October 24, 2017.
4. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2—), advanced breast cancer (ABC). J Clin Oncol. 2017;35(suppl; abstr 1038). meetinglibrary.asco.org/record/153081/abstract.
5. Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract 236O_PR. doi: 10.1093/annonc/mdx365.
6. CDK 4/6 inhibitors in metastatic breast cancer. OncLive^® website. www.onclive.com/insights/cdk-inhibitors-breast-cancer/cdk-4-6-inhibitors-in-metastatic-breast-cancer. Published October 2, 2017. Accessed October 24, 2017.
7. Saura C, De Azambuja E, Hlauschek D, et al. Primary results of LORELEI: a phase II randomized, double-blind study of neoadjuvant letrozole (LET) plus taselisib versus LET plus placebo (PLA) in postmenopausal patients (pts) with ER+/HER2-negative early breast cancer (EBC). Presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract LBA10_PR. doi: 10.1093/ annonc/mdx440.001.
8. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128-2135. doi: 10.1200/ JCO.2012.43.7251.
9. Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063);2997-3005. doi: 10.1016/S0140-6736(16)32389-3