Novel Agents May Address Endocrine Therapy Resistance


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Hope S. Rugo, MD

Future Approaches in Endocrine-Positive Disease

These studies of novel agents represent a new paradigm in the treatment of metastatic estrogen receptor–positive breast cancer, with more to come.

—Hope S. Rugo, MD

Progress has recently been swift in the development of new drugs to improve the response to hormone therapy in breast cancer, according to Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. At the 2014 Breast Cancer Symposium in San Francisco, Dr. Rugo described these promising agents and their effect on acquired resistance.

Resistance to endocrine therapy is an impediment in the treatment of breast cancer patients with hormone receptor–positive tumors. This is caused by multiple heterogeneous alterations in the tumor and tumor environment, including “loss” of estrogen receptor–alpha and upregulation of alternative signal transduction pathways. The first of these obstacles might be tackled through histone deacetylase (HDAC) inhibition, whereas the second might be ameliorated by antagonizing the PI3K/AKT/mTOR pathway (which is altered in up to 50% of estrogen receptor–positive tumors) and blocking cyclin-dependent kinases (CDKs) and growth factor receptors, Dr. Rugo ­suggested.

The most promising agents for these strategies are inhibitors of the PI3K pathway, CDK 4/6 inhibitors, and HDAC inhibitors, according to Dr. Rugo. She noted, “We still have a desperate need for biomarkers to identify tumors that are most likely to benefit from these novel approaches.”

Everolimus Plus Exemestane

The demonstration of a 50% reduction in progression when the mTOR inhibitor everolimus ­(Afinitor) was combined with exemestane in ­BOLERO-2 led to the U.S. Food and Drug Administration (FDA) approval of this combination in women who had disease progression on nonsteroidal aromatase inhibitors.1 Since toxicity can be an issue with everolimus, efforts to identify a predictive biomarker have been robust, but futile.2

“But we are making progress,” she emphasized. “We found that we can improve outcome by adding targeted agents. Now, we move to the next steps.”

HDAC Inhibitor Plus Exemestane

The phase II ENCORE 301 trial evaluated exemestane with and without the HDAC inhibitor entinostat in women progressing after treatment with a nonsteroidal aromatase inhibitor.3 The addition of entinostat led to a 10-month improvement in overall survival, from 19.8 months with exemestane alone to 28.1 months with the combination (hazard ratio [HR] = 0.59, P = .04).

Because of these impressive findings, the FDA granted entinostat a Breakthrough Therapy designation. The phase III E2112 trial will further evaluate entinostat plus exemestane in 600 metastatic patients. Importantly, prior treatment with everolimus is allowed in this study.

With HDAC inhibition, epigenetic changes may lead to the loss of estrogen receptor–alpha and make it more difficult to inhibit this receptor. Histone deacetylation could boost the reappearance of estrogen receptor–alpha transcription; it also “opens up” the structure of DNA to turn the relevant genes on, she explained.

PI3K Inhibitors

There is more than one way to target the PI3K/mTOR pathway, including the pan-PI3K inhibitor buparlisib (BKM120) and the alpha-specific PI3K inhibitor alpelisib (BYL719), she said.

In a study led by investigators from Vanderbilt University in Nashville, buparlisib shrank tumors in 2 of 20 advanced breast cancer patients and stabilized disease in 6, producing a metabolic partial response in 18FDG-PET scans in 9 patients.4

“This is a reasonably well tolerated and interesting agent, and these exciting data have led to a number of trials,” she said. The drug will be evaluated for its differential benefits based on PI3K mutation status.

BELLE-2 has enrolled 1,060 estrogen receptor–positive, aromatase inhibitor–resistant, mTOR inhibitor-naive patients to receive fulvestrant (Faslodex) plus buparlisib or placebo. BELLE-3 will evaluate this combination after prior treatment with an mTOR inhibitor. NEOBELLE will evaluate both buparlisib and alpelisib (alone and in combination), plus letrozole. A phase Ib study of alpelisib alone and in combination with fulvestrant had been completed by the time of the Breast Cancer Symposium, and results of first data were presented at the ESMO Congress in Madrid.

The phase II FERGI trial is evaluating the pan-PI3K inhibitor pictilisib (GDC-0941) in combination with fulvestrant in women with prior aromatase inhibitor exposure; the arm evaluating GDC-0980, a dual PI3K/mTOR inhibitor, was closed due to toxicity. The alpha-specific PI3K inhibitor GDC-0032 is in phase I development.

Cyclin-Dependent Kinases

Cyclin-dependent kinases, which inhibit the tumor suppressor Rb protein, are a very active area of research and drug development. Rb plays a pivotal role in the negative control of the cell cycle. Hyperphosphorylation of Rb is mediated in the G1 phase by CDK4 and CDK6 interacting with cyclin D1, and this results in tumor progression.

Palbociclib, a CDK4/6 inhibitor, induces cell-cycle arrest and allows Rb to bounce back. In breast cancer cell lines, single-agent palbociclib was most inhibitory in luminal and HER2-amplified tumors, a preclinical finding that could help tailor therapy.

In the recent PALOMA-1 trial, the addition of palbociclib to letrozole led to a significant improvement in progression-free survival, from 10.2 to 20.2 months (HR = .488; P = .0004).5 Based on these results, palbociclib earned a Breakthrough Therapy designation.

Additional trials of palbociclib are underway, including an international registration study of 480 patients in the first-line setting (in combination with letrozole), a phase III trial (in combination with fulvestrant), a postneoadjuvant study (in combination with an aromatase inhibitor), an adjuvant pilot trial in high-risk patients, a study in patients with prior PI3K inhibitor therapy (in combination with fulvestrant or tamoxifen), and others.

Other CDK inhibitors in development include LEE011, which is being studied in combination with letrozole, with exemestane, with exemestane plus everolimus, and with alpelisib. “Preclinical data suggest there is marked synergy for a CDK inhibitor combined with an alpha-specific PI3K inhibitor, so these studies are very interesting,” Dr. Rugo indicated.

Abemaciclib (LY2835219) has also demonstrated single-agent efficacy and a different toxicity profile than palbociclib: less neutropenia but more diarrhea.6 It is being studied as a single agent in a phase II trial of heavily pretreated patients, and in combination with fulvestrant in a phase III trial, with an eye toward registration, she said.

FGFR Inhibitors

Fibroblast growth factor receptor (FGFR) inhibitors may also prove valuable in treating resistant tumors. Currently, there are two drugs to watch: dovitinib is being evaluated in a phase II study in combination with fulvestrant in patients with FGFR-amplified and nonamplified tumors, while lucitanib will be studied in a phase II monotherapy trial of patients with FGFR-amplified tumors.

Concluding her talk, Dr. Rugo said, “We have exemestane and everolimus approved in the second and third line for patients with previous exposure to aromatase inhibitors, and we are looking forward to the next step. These studies of novel agents represent a new paradigm in the treatment of metastatic estrogen receptor–positive breast cancer, with more to come.” ■

Disclosure: Dr. Rugo receives research funding to UCSF from Novartis, Pfizer, and Lily.

References

1. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

2. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Presented June 3, 2013.

3. 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 31:2128-2135, 2013.

4. Mayer IA, Abramson VG, Isakoff SJ, et al: Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 32:1202-1209, 2014.

5. Finn RS, Crown JP, Lang I, et al: Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1; TRIO-18). American Association for Cancer Research Annual Meeting. Abstract CT101. Presented April 6, 2014.

6. Patnaik A, Rosen LS, Tolaney SM, et al: LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer. ASCO Annual Meeting. Abstract 534. Presented June 1, 2014.



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