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Three ASCO15 Late-Breaking Endocrine Therapy Updates in Advanced Breast Cancer

Carlson, Robert H.

doi: 10.1097/01.COT.0000470865.49728.1b
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CHICAGO—Anastrozole, letrozole, and fulvestrant, standard endocrine treatments for advanced breast cancer, were featured in three late-breaking abstracts presented in an oral abstract session here at the American Society of Clinical Oncology Annual Meeting.

The Phase III NSABP B-35 trial, comparing anastrozole with tamoxifen for prevention of breast cancer recurrence in women with ductal carcinoma in situ (DCIS) (Abstract LBA500), found anastrozole to be more effective in preventing DCIS and other breast cancer events.

In the multicenter, open label Phase III CALGB (Alliance) 40503 trial, bevacizumab was added to first-line letrozole in patients with hormone-receptor positive advanced breast cancer to test the hypothesis that anti-VEGF therapy could delay progression on endocrine therapy (Abstract LBA501). The study showed that the combination slightly increased progression-free survival but not overall survival, and also caused more toxicity.

And in the PALOMA-3 study, the CDK4/6 inhibitor palbociclib plus fulvestrant improved progression-free survival rates compared with use of fulvestrant alone in women with hormone receptor-positive HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapy (Abstract LBA502).

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NSABP B-35: Aromatase Inhibitor Superior

NSABP B-35, the first Phase III trial of anastrozole versus tamoxifen for DCIS, showed that anastrozole produced a significantly longer breast cancer-free interval, defined as the time from randomization to any breast cancer event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS.

“Anastrozole is quite a suitable drug for DCIS,” said the study's lead author, Richard G. Margolese, MD, Professor and Director of Surgical Oncology at The Jewish General Hospital of McGill University in Montreal, Canada, who presented the data. “We now have another option for adjuvant therapy for DCIS.”

The 10-year breast cancer-free survival rate was 93.5 percent in the anastrozole group versus 89.2 percent in the tamoxifen group, he reported, noting that both drugs have an acceptable safety profile: Severe adverse reactions to either drug are uncommon, although such problems were slightly less with anastrozole.

“Anastrozole might turn out to be the preferable option for adjuvant treatment of DCIS, especially in women in whom there is concern about thromboembolism or uterine cancer because of various features in that person's history,” Margolese said.

Patients in the study were postmenopausal, with ER and/or PR-positive disease, and had undergone wide local excision with negative margins and whole breast radiation. They were stratified in the trial by age—under 60 and 60 and over.

Patients were randomly assigned to receive tamoxifen at 20 mg/day and placebo for five years (1,538 patients) or anastrozole at 1 mg/day and placebo (1,539) for five years.

With a median follow-up of 8.6 years, 114 breast cancers were detected in the tamoxifen group compared with 84 in the anastrozole group. This included recurrences of DCIS as well as development of de novo DCIS or invasive breast cancer in either breast.

“In women younger than 60, the incidence was decreased conspicuously with anastrozole—about 95 percent at 10 years versus 88 percent for tamoxifen,” Margolese said. Women older than 60 had very similar results: 92 percent for anastrozole and 90 percent for tamoxifen.

He said there is no good explanation for this virtual equivalence of the two drugs among older women: “It requires more biologic probing.”

There were fewer ipsilateral recurrences in the anastrozole study arm—2.8 percent (0.9% invasive and 1.9% DCIS) versus 3.4 percent in the tamoxifen arm (1.4% and 2.0%, respectively). Contralateral breast cancer was also less in the anastrozole arm; 2.4 percent (1.3% and 1.1%) versus 3.5 percent for tamoxifen (2.3% and 1.2%).

Uterine cancers occurred far more frequently with tamoxifen, as expected: 1.7 versus 0.8 percent for anastrozole.

However, Margolese said that this was infrequent, representing only 1.6 percent of all patients.

Osteoporotic fractures were also infrequent, but more common among patients in the anastrozole arm—6.9 versus 5.0 percent for tamoxifen. “The number of osteoporotic fractures would be expected to be higher with anastrozole because it inhibits the production of estrogen,” Margolese said, adding, though, that the results here are not statistically significant.

“The good news is that tamoxifen and anastrozole are both very effective, but it seems that women have better chances of staying well with anastrozole,” Margolese said at an ASCO news conference that highlighted the study. “Women should also consider the differences in side effects when discussing treatment options with their doctors.”

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‘Consider Full Range of Options’

Don S. Dizon, MD, Clinical Co-Director of Gynecologic Oncology and Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, was the designated ASCO expert at the news conference, and gave his perspective about the study: “Women with DCIS already have several great treatment options, and now they have one more. Aromatase inhibitors offer important advantages, but patients and their doctors should still consider the full range of options, including tamoxifen, or even foregoing adjuvant treatment, as every approach carries its own risks and benefits.”

Also commenting, in an interview before the meeting, ASCO 2014-2015 President Peter Paul Yu, MD, Director of Cancer Research at Palo Alto Medical Foundation, said: “We have seen in the metastatic setting that aromatase inhibitors are superior in response rates to tamoxifen, and we have seen in the adjuvant setting that aromatase inhibitors are better than tamoxifen. This is the next stage, chemopreventive treatment for DCIS.”

Yu said the improvement in incidence of adverse events in this trial is similar to what has been seen in other studies comparing aromatase inhibitors and tamoxifen.

And cost is not a great concern with either of these two treatments, Yu noted, since both drugs are generic.

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CALGB/Alliance 40503: No Survival Advantage for Bevacizumab

High vascular endothelial growth factor (VEGF) levels in breast tumors have been associated with decreased response to endocrine therapy. Now, a multicenter, open-label Phase III trial that added bevacizumab to first-line letrozole in patients with hormone-receptor positive advanced breast cancer has tested the hypothesis that anti-VEGF therapy may delay progression.

In the efficacy analysis of CALGB/Alliance 40503 presented here by Maura N. Dickler, MD, Associate Member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, the trial began accruing patients in 2008, before bevacizumab lost its accelerated approval for breast cancer from the Food and Drug Administration in 2011 (because studies showed no effect on overall survival).

The 343 patients in the study had a median age of 58, with a range of 25 to 87. Treatment consisted of letrozole at 2.5 mg orally daily or letrozole plus bevacizumab at 15 mg/kg intravenously every three weeks. The primary endpoint was progression-free survival; secondary endpoints were response rate, clinical benefit rate, overall survival rate, and adverse events.

At 39 months of follow-up, median progression-free survival for patients receiving letrozole plus bevacizumab was 20 months, versus 16 months for those on letrozole alone. Dickler said there was no significant difference between the two study arms in overall survival—47 months for letrozole plus bevacizumab versus 41 months for letrozole alone. But, there was a significant difference in grade 3/4 toxicities: 23 percent of patients taking the combination had hypertension versus just two percent for those on letrozole alone; and proteinuria was also higher, in 11 versus zero percent, respectively.

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PALOMA-3: Checkpoint Is Key Target

Resistance to endocrine treatment remains a major clinical problem for patients with hormone receptor positive breast cancer. Researchers in the PALOMA-3 study, funded by Pfizer, hypothesized that checkpoint inhibition might “unleash” the immune system to overcome this resistance.

The study added the CDK4/6 checkpoint inhibitor palbociclib to fulvestrant, and the combination was shown to improve progression-free survival compared with placebo and fulvestrant in women with HR-positive HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapy. The benefit from palbociclib was demonstrated across all pre-specified subgroups, including in both pre- and post-menopausal women, said the lead study author, Nicholas C. Turner, MD, a consultant medical oncologist at The Royal Marsden and a team leader at The Institute of Cancer Research in London.

Palbociclib is an orally selective drug that inhibits breast cancer cell proliferation and growth by preventing cell cycle progression from the G1 to S phase.

Turner explained that in a prior Phase II study, palbociclib in combination with letrozole significantly increased progression-free survival over letrozole alone in newly diagnosed advanced HR-positive breast cancer (Finn et al: Lancet Oncol 2015;16:25-35).

PALOMA-3, the first Phase III study of a CDK4/6 inhibitor in breast cancer, identified and confirmed that CDK4/6 is a key target in HR-positive breast cancer, he said, noting that the growth of HR-positive breast cancer is dependent on the cyclin dependent kinases CDK4/6 that promote the G1-S phase cell-cycle progression.

The trial included 521 patients in 17 countries in North American, Asia, and Europe, with both pre- and post-menopausal women. All had HR-positive, HER2-negative advanced breast cancer and had disease progression on prior endocrine therapy.

The trial was stopped early based on the efficacy seen in the interim analysis. At the time of that analysis, the median time to disease progression was 9.2 months in the palbociclib arm compared with 3.8 months in the placebo arm, he reported. Comparable benefits were seen in both the premenopausal and postmenopausal women.

“The curves separate early and then continue to separate with ongoing follow-up,” he said. “The palbociclib-fulvestrant combination was well tolerated, although there were frequent hematologic side effects: neutropenia was seen in 79 percent of patients on palbociclib and fulvestrant, and leukopenia in 46 percent.”

But the incidence of febrile neutropenia was very rare, he added—0.6 percent in both arms of the study.

Symptomatic adverse events with palbociclib were largely similar to placebo, with a small increase in fatigue, alopecia, and infections, but serious adverse events were the same in both arms. Discontinuation due to adverse events was also similar.

“This relatively easy-to-take new drug can substantially delay the point when women need to start chemotherapy, making this an exciting new approach for women,” Turner said.

The drug received Accelerated Approval from the FDA earlier this year (OT 3/10/15 issue), for use in combination with letrozole for women with metastatic ER-positive, HER2-negative breast cancer who have not yet received hormonal therapy for their metastatic disease. The approval was granted based on the results of the Phase II PALOMA-1 study.

In the interview before the ASCO meeting, Yu noted that palbociclib is already available and so could be prescribed off label: “So this is potentially a practice-changing abstract that we want to highlight so that doctors and patients are aware they have this choice.”

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Perspective on the Studies from Joseph Sparano

CHICAGO—The three presentations each focus on therapeutically targeting three different hallmarks of cancer, including the tumor and the microenvironment, said the Discussant, Joseph A. Sparano, MD, Professor of Medicine and Obstetrics, Gynecology, and Women's Health at Albert Einstein College of Medicine and Associate Chairman for Clinical Research in the Department of Oncology at Montefiore Medical Center.

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CALGB/Alliance 40503

Beginning with microenvironment, Sparano said Maura Dickler's presentation showed that the addition of the anti-EGFR agent bevacizumab significantly extended median progression-free survival when added to first-line endocrine therapy, reducing the hazard rate for progression by 26 percent. “This translated into about a four-month absolute improvement in median profession-free survival, but with no impact on overall survival.”

These results were similar to those seen in previous trials when bevacizumab was added to first-line endocrine therapy, he said, and show very consistent results, indicating a marginal benefit and added toxicity: “There is currently no role for bevacizumab [in breast cancer] in either the adjuvant or neoadjuvant setting outside the context of a clinical trial.”

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Antiestrogen Therapy

Regarding the NSABP B35 study, he noted that anti-estrogen therapy is a cornerstone in the management of ER-positive disease, and that selective estrogen receptor modulators (SERMs) like tamoxifen or degraders like fulvestrant bind to the estrogen receptor, thus competitively inhibiting binding of estrogen to the estrogen receptor. In contrast, aromatase inhibitors block the conversion of androgens to estrogens, resulting in estrogen depletion in postmenopausal women for whom it is a major source of endogenous estrogen, more effectively reversing the genomic-mediated effects.

“In the NSABP B35 trial, these two strategies were directly compared for the first time in postmenopausal women with ER-positive and/or PR-positive DCIS who had undergone wide local excision with negative margins and whole breast radiation.” As expected, anastrozole was associated with fewer uterine cancers and thromboembolic events, and somewhat more osteoporotic fractures, and a higher rate of arthralgias.

“These findings provide additional evidence that estrogen deprivations are a more effective anti-estrogenic strategy than a SERM, including in younger women,” Sparano said.

He noted that it has been known for more than two decades that aromatase inhibitors are more effective than tamoxifen or megesterol in postmenopausal women with metastatic disease, and for more than a decade that aromatase inhibitors are more effective than tamoxifen as adjuvant therapy in postmenopausal women.

It has also been known that extended adjuvant therapy with an aromatase inhibitor following tamoxifen is most effective in women who were premenopausal at the time of diagnosis. And most recently it has been learned that ovarian suppression plus an aromatase inhibitor is more effective than tamoxifen as adjuvant therapy in premenopausal women at high risk for recurrence, including for women under the age of 35 who are node-positive, treated with chemotherapy.

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Take-Home Points

Sparano's take-home messages:

  • Anastrozole and probably other aromatase inhibitors are a good option for preventing ipsilateral recurrence, but more importantly, for preventing contralateral cancers and DCIS: “Anastrozole is perhaps best suited for younger postmenopausal women with an intact contralateral breast and/or uterus, or a prior history of thrombosis;”
  • The role of bevacizumab in breast cancer remains uncertain: “A modest effect in prolonging progression-free survival, when added to aromatase inhibitors, has now been seen in two trials, but better alternatives are now available; the most effective combination in prolonging PFS was when bevacizumab was added to weekly paclitaxel;”
  • There is no role for the use of bevacizumab in the adjuvant or neoadjuvant setting; and
  • CDK4/6 inhibitors represent an important therapeutic advance in ER-positive metastatic breast cancer: “This represents an entirely new therapeutic modality, and we are just beginning to understand how to appropriately use these agents.”
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Cost Concerns

He concluded by raising the issue of the high cost of cancer drugs overall as well as related to the drugs in these breast cancer studies. “The escalating costs pose a main challenge for patients, the community of health care providers, and the entire health care ecosystem,” he said.

“When considering the therapeutic index of new and existing drugs, we as a community need to have a deeper understanding of the cost of therapies that we prescribe, and the impact on the patients that we serve. The future is calling for us to consider value, not just the components of value, in caring for our patients. And the future is now.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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