In Breast Cancer, Targeted Agents Boost Hormonal Therapies

OncologyLive, October 2012, Volume 13, Issue 10

Novel combinations of hormonal therapies with targeted agents show promise for improved outcomes and are likely to become part of a new paradigm for managing patients.

Agustin A. Garcia, MD

Although hormonal therapy has been long established in the treatment of breast cancer, novel combinations with targeted agents show promise for improved outcomes and are likely to become part of a new paradigm for managing patients.

The success of everolimus (Afinitor) in combination with exemestane has helped pave the way for such strategies, and agents aimed at various mechanisms of resistance to endocrine therapy are being explored, according to Agustin A. Garcia, MD, MMM, associate professor of Medicine at the Keck School of Medicine of the University of Southern California, Los Angeles.

In July, the FDA approved everolimus for use with exemestane to treat postmenopausal women with hormone receptor (HR)-positive, HER2-negative breast cancer whose disease has progressed after prior treatment with aromatase inhibitors (AIs). Everolimus targets mammalian target of rapamycin (mTOR) while exemestane is an AI.

In a presentation and interview at the Targeted Therapies congress, Garcia noted that the BOLERO-2 trial that led to the new everolimus indication has opened the door to new ways of thinking about boosting the effectiveness of endocrine therapy.

“We have to look very carefully into changing our approach to how we treat those women. Typically, we treated them with single-agent sequential therapies, usually until they developed clear resistance to endocrine therapy,” said Garcia. “What the BOLERO-2 trial shows us is that combination therapy may be indicated or appropriate for at least a group of those patients.”

Garcia noted that endocrine therapy has been employed as breast cancer treatment for more than a century, since Scottish surgeon Sir George Thomas Beatson first propounded the theory that oophorectomy was effective in 1896. Since then, many drugs with varying mechanisms of action have been developed to interrupt hormonal activity in breast cancer patients.

Hormonal therapy has become a “cornerstone” of treatment for HR-positive disease, showing efficacy in metastatic breast cancer as well as in ductal carcinoma in situ and in primary breast cancer prevention. However, a significant number of patients develop de novo and acquired resistance, Garcia said.

“We’re becoming better at understanding hormonal therapy as a targeted treatment. We still have to better understand the mechanism of resistance,” said Garcia. “Why is it that there’s a subset of patients who never respond to hormonal therapy? Why is it that virtually every patient who’s responding to hormonal therapy in the metastatic setting will eventually acquire resistance? That’s where we’re still in a very early process.”

Garcia said researchers have identified mechanisms of resistance in the tumor microenvironment, namely the estrogen receptor (ER) and its coregulators, and in cell-signaling molecules and growth factor receptor pathways associated with the tumor itself.

Research is under way to target these pathways both with novel agents and existing drugs in combination with hormonal therapies (Table).

Table. Combination Studies of Targeted Agents and Hormonal Therapies in Breast Cancer

Target

Agent

Sponsors

Stage

Insulin-like growth factor type 1 (IGF-1)

Ganitumab (AMG 479)

Foundation for the National Institutes of Health

Phase II (NCT01042379)

MEDI-573

MedImmune

Phase I (NCT01446159)

Fibroblast growth factor receptor (FGFR)

AZD4547

AstraZeneca

Phase I/II (NCT01202591)

Epidermal growth factor family and HER2

Gefitinib (Iressa)

AstraZeneca

Phase II (NCT00077025)

Trastuzumab (Herceptin)

Genentech/Roche

Phase III (NCT00022672)

MM-121

Merrimack Pharmaceuticals

Phase II (NCT01151046)

Cyclin dependent kinase (CDK) 4/6

PD-0332991

Pfizer

Phase I/II (NCT00721409)

mTOR/PI3K

Everolimus (Afinitor)

Novartis

Phase II (NCT01698918)

XL147

XL765

Sanofi

Phase I/II (NCT01082068)

Histone deacetylase(HDAC)

Entinostat (SNDX-275)

Syndax Pharmaceuticals

Phase II (NCT00676663)

Vascular endothelial growth factor/ angiogenesis

Bevacizumab (Avastin)

Cancer and Leukemia Group B/ National Cancer Institute

Phase III (NCT00601900)

mTOR indicates mammalian target of rapamycin; PI3K, phosphatidylinositol 3 kinase.

In the realm of emerging research, Garcia said he is awaiting the results of the phase III Cancer and Leukemia Group B (CALGB) 40503 trial, in which 442 patients were randomized to receive tamoxifen or letrozole with or without bevacizumab (Avastin). The completion date for data collection is June 2013.

Garcia said the rationale for using bevacizumab in combination with hormonal therapies is stronger than it is for combining the drug with chemotherapy. “We know that in hormonal therapy, angiogenesis becomes a very important mechanism of growth, so it seems reasonable to combine hormonal therapies with inhibitors of angiogenesis,” he said.

For more immediate clinical use, Garcia cited three combinations he finds particularly compelling:

Anastrozole Plus Fulvestrant

In the SWOG S0226 trial, the combination of anastrozole (Arimidex) and fulvestrant (Faslodex) demonstrated a significant advantage in progression-free survival (PFS), the primary endpoint, when compared with anastrozole alone. Anastrozole is a nonsteroidal aromatase inhibitor, while fulvestrant is an ER antagonist.

The phase III trial involved 707 postmenopausal women with metastatic breast cancer that was either ER-positive or progesterone receptor-positive. Approximately 40% of the participants had received prior adjuvant tamoxifen treatment and 33.4% had undergone prior adjuvant chemotherapy.

The median PFS for those treated with the combination was 15.0 months, compared with 13.5 months for those who received anastrozole alone, even though the fulvestrant dose used in the trial was below the current standard, according to findings investigators reported in The New England Journal of Medicine in August (2012;367(5):435-444).

The results were more pronounced when the subset of patients who had not received prior tamoxifen were examined, Garcia said. For this cohort, the median PFS with the combination was 17.0 months, compared with 12.6 months for those who had received anastrozole alone.

Similarly, median overall survival (OS) with the combination was 47.7 months both for the group as a whole and the subset without prior tamoxifen, compared with OS of 41.3 months overall and 39.7 months for the subset, respectively, in the single-agent group.

However, the positive findings that the combination achieved were contradicted by the FACT trial, which found no clinical advantage for it. The time to progression, the primary endpoint of FACT, was 10.8 months for those who received the combination, compared with 10.2 months for anastrozole alone, results reported in the Journal of Clinical Oncology indicate (published online ahead of print February 27, 2012, doi:10.1200/JCO.2011.38.1095). Median PFS was 15.0 months with the combination and 13.5 months with anastrozole alone.

Garcia said researchers believe the two studies delivered such different results because of the prior treatment the patients had received. In SWOG S0226, a large proportion of the participants had not received the ER antagonist tamoxifen. By contrast, in FACT, which was conducted in Europe, 69% in the combination arm had received prior antiestrogens.

“The belief right now is that maybe this combination is particularly effective in those patients who are completely naïve to hormonal therapies,” said Garcia, adding that further study is needed.

Everolimus Plus Exemestane

The BOLERO-2 trial, which generated excitement at the CTRC-AACR San Antonio Breast Cancer Symposium in December 2011, prompted the FDA to approve the combination of everolimus and exemestane less than eight months later (Figure).

Figure. BOLERO-2: Phase III Trial of Exemestane With or Without Everolimus in Advanced Breast Cancer

N = 724

  • Postmenopausal ER+
  • Unresectable locally advanced or metastatic BC
  • Recurrence or progression after letrozole or anastrozole

R

2:1

EVE 10 mg daily

+

EXE 25 mg daily (n = 485)

Placebo

+

EXE 25 mg daily (n = 239)

Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases

Endpoints:

— Primary: PFS (local assessment)

— Secondary: OS, ORR, QOL, safety, bone markers, PK

BC indicates breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival;

PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.

Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

The phase III trial demonstrated that the dual inhibition therapy resulted in median PFS of 7.4 months by local assessment and 11 months by central evaluation, as opposed to 3.2 months and 4.1 months with those two assessment measures, respectively, for placebo plus exemestane (N Eng J Med. 2012;366[6]:520-529).

“There’s absolutely no question in my mind that adding everolimus to exemestane markedly improves the efficacy of the therapy,” said Garcia, adding that few new developments in cancer treatment have been associated with such a dramatic improvement in outcome.

As it stands now, Garcia believes everolimus should be introduced “relatively earlier in the management of breast cancer, following the indication of patients who have progressed” after AI therapy, particularly a nonsteroidal AI. “I don’t think it should be a combination that we reserve as our 10th hormonal therapy.”

Tamoxifen Plus Everolimus

In the TAMRAD study, the combination of tamoxifen plus everolimus was compared with tamoxifen alone, with a six-month clinical benefit rate (CBR) as the primary endpoint. The randomized, phase II study involved 111 postmenopausal women who had HR-positive, HER2-negative metastatic breast cancer.

Overall, the combination delivered a six-month CBR of 61% compared with a 42% CBR for the single agent, investigators reported in the Journal of Clinical Oncology [2012;30(22):2718-2724).

Researchers further stratified participants by their prior responses to AI therapy in an effort to determine whether primary or secondary resistance to hormonal therapy was a factor.

Primary resistance was defined as relapse during or ≤6 months after completion of adjuvant AI treatment or progression in the metastatic setting ≤6 months following the start of AI treatment. Patients with secondary resistance had relapsed either >6 months after adjuvant AI therapy or after they had been responding to AI therapy in the metastatic setting for ≥6 months.

The results indicate that patients with secondary hormone resistance derived more benefit, with a 74% CBR in the combination arm versus a 48% CBR with tamoxifen alone. Among the primary resistance cohort, the CBR was 46% in the combination group, compared with 36% for the single agent.

Garcia said this combination is “important to consider, although not FDA-approved.”