PER Pulse™ Recap
A PER Pulse™ Recap summarizes data presented at the 2014 Annual Meeting of the American Association for Cancer Research on current advances in hormone receptor–positive breast cancer (HR+ BC) and current investigational approaches in hormone receptor–positive breast cancer (HR+ BC) that are in late-stage clinical development.
PER Pulse™ Recap
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PER Pulse™ Recap:
The following PER Pulse™ Recap summarizes data presented at national and international oncology meetings on current advances in hormone receptor–positive breast cancer (HR+ BC).
Aromatase Inhibitors as Adjuvant Therapy in Premenopausal Women
Aromatase inhibitors (AIs) have recently emerged as a more effective adjuvant strategy than tamoxifen (TAM) in postmenopausal women with HR+ BC,1
and their use is now being investigated in premenopausal women with HR+ BC.
A joint analysis of data from two randomized phase III clinical trials – TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) – showed that in premenopausal women with HR+ BC (n=4690), 5-year disease-free survival was significantly improved in those who received the AI exemestane (EXE) in combination with ovarian function suppression (OFS) compared with those who received TAM + OFS (91.1% vs 87.3%, respectively (hazard ratio [HR] = 0.72; 95% confidence interval [CI], 0.60-0.86; P
Furthermore, the benefit of EXE + OFS vs. TAM + OFS was similar for the BC-free interval and distant recurrence-free interval, but not for overall survival. Grade 3/4 adverse events (AEs) were reported in 31% of women receiving EXE + OFS and 29% of those receiving TAM + OFS, a safety profile that is comparable to that reported in postmenopausal women.
Endocrine Therapy Plus mTOR Inhibition
The mammalian target of rapamycin (mTOR) pathway plays an important role in the growth and progression of BC and in the development of endocrine resistance. In 2012, the mTOR inhibitor everolimus (EVE), in combination with EXE, was approved for the treatment of postmenopausal women with HR+/HER2-negative (HER-) advanced BC whose disease had recurred or progressed after AI therapy.3
The approval was based in large part on findings from the pivotal BOLERO-2 trial, which showed that EVE + EXE versus placebo + EXE more than doubled median progression-free survival at median follow-up of 18 months (7.8 vs 3.2 months, respectively; HR = 0.45; 95% CI, 0.38-0.54; P
Of interest, interim data from the German noninterventional BRAWO study in 866 assessable patients with advanced or metastatic HR+/HER2- BC showed that those who received EVE + EXE as first- or second-line therapy were less likely to experience any AE than were those who received the treatment in later lines of therapy (68.7% vs 81.4%, respectively ; P
Markopoulos C. Minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: Efficacy review of AI trials. Cancer Metastasis Rev. 2010;29(4):581-590.
Pagani O, Regan MM, Walley B, et al. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. J Clin Oncol. 2014;32(suppl 5; abstr LBA1).
Beck JT, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2. Breast Cancer Res Treat. 2014;143:459-467.
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR+ breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870-884.
Lueftner D, Schuetz F, Grischke E-M, et al. Breast cancer treatment with everolimus and exemestane for ER+ women: Results of the first interim analysis of the noninterventional trial BRAWO. J Clin Oncol. 2014:32(suppl 5; abstr 578).
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PER Pulse™ Recap:
The following PER Pulse™ Recap summarizes data presented at the 2014 Annual Meeting of the American Association for Cancer Research on current investigational approaches in hormone receptor–positive breast cancer (HR+ BC) that are in late-stage clinical development.
Investigational Approaches in Late-Stage Clinical Development
Several investigational approaches for HR+ BC are in late-stage clinical development, including the use of palbociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6) that has received Breakthrough Therapy designation from the US Food and Drug Administration.1
PALOMA-1, a randomized phase II study in 165 postmenopausal women with metastatic BC, was conducted to compare the efficacy and safety of palbociclib + letrozole versus letrozole alone.2
Sixty-six participants in the study had HR+/HER2-negative (HER2-) metastatic BC, and 99 participants had HR+/HER2- metastatic BC with alterations in cyclin D1
, both of which are markers of palbociclib sensitivity. The design of the study was based on preclinical data showing that HR+ BC cells depend on CDK 4/6 for growth and are sensitive to CDK 4/6 inhibition.
First-line treatment with palbociclib + letrozole was shown to be associated with significantly improved progression-free survival compared with letrozole alone (20.2 vs 10.2 months, respectively); the findings represent a 51% reduction in the risk of disease progression when palbociclib is added to letrozole. Reported adverse events (AEs) included neutropenia, leukopenia, fatigue, and anemia.
At present, palbociclib is also being investigated in combination with other agents in several phase III trials:
PALOMA-2 (with letrozole in late-stage metastatic BC)
PALOMA-3 (with fulvestrant in late-stage metastatic BC)
PENELOPE-B (with standard endocrine therapy in some early-stage BC)
PEARL (with exemestane in patients with HR+/HER2- metastatic BC who have resistance to nonsteroidal aromatase inhibitors)
"As for current investigational approaches, CDK 4/6 inhibitors appear to be a very exciting group of drugs," said Ruth O’Regan, MD, Winship Cancer Institute, Atlanta, GA. "Palbociclib is furthest along, with positive results coming out of randomized trials and very minor toxicities thus far. A number of additional CDK inhibitors look very promising for improving patient outcomes, the PI3-kinase inhibitors among them, which also appear to be very well tolerated."
Pfizer. Pfizer’s palbociclib (PD-0332991) receives Food and Drug Administration Breakthrough Therapy designation for potential treatment of patients with breast cancer. Available at: http://press.pfizer.com/press-release/pfizers-palbociclib-pd-0332991-receives-food-and-drug-administration-breakthrough-ther. Accessed August 8, 2014.
American Association for Cancer Research. Palbociclib shows promising results in patients with hormone receptor-positive metastatic breast cancer. Available at: http://aacrnews.wordpress.com/2014/04/06/palbociclib-shows-promising-results-in-patients-with-hormone-receptor-positive-metastatic-breast-cancer/. Accessed August 8, 2014.
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