High dose Fulvestrant more effective than anastrozol for 1st line mets

[Rich66]

Robertson JFR et al. – First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.
Methods

• Phase II, randomized, open-label, multicenter study
• HD fulvestrant regimen (500 mg/mo + 500 mg on d 14 of mo 1) vs. anastrozole (1 mg/d)
• Primary analysis 6 mos after last patient assigned

Results

• CBR was similar for fulvestrant HD and anastrozole (72.5% vs. 67.0%, respectively)
• ORR was similar for fulvestrant HD and anastrozole (36.0% vs. 35.5%, respectively)
• TTP was significantly longer for fulvestrant vs. anastrozole (median TTP for fulvestrant HD was not reached; 12.5 mos for anastrozole)
• Duration of OR and CB favored fulvestrant HD
• Both treatments were well-tolerated, with no significant differences in the incidence of pre-specified adverse events

Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study

John F.R. Robertson,^* Antonio Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan Macpherson, Justin Lindemann, and Matthew J. Ellis
From the Division of Breast Surgery, University of Nottingham, Nottingham; Department of Oncology, Ninewells Hospital and Medical School, Dundee; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom; Hospital Arnau de Vilanova, Lérida, Spain; Centrum Onkologii, Instytut im M. Skodowskiej-Curie, Krakow, Poland; Fackultni Nemocnice Ostrava, Radioterapeutická klinika, Ostrava-Poruba, Czech Republic; Washington University School of Medicine, St Louis, MO.

^* To whom correspondence should be addressed. E-mail: john.robertson@nottingham.ac.uk

Purpose: To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor–positive breast cancer in postmenopausal women.
Patients and Methods: FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.
Results: CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.
Conclusion: First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.



CONFIRM Trial: Fulvestrant 500 mg Better Than Standard Dosing

Elsevier Global Medical News. 2009 Dec 11, B Jancin

SAN ANTONIO (EGMN) - Fulvestrant at 500 mg per dose is significantly more effective and no more toxic than the approved 250-mg dose in postmenopausal women with estrogen receptor-positive advanced breast cancer, according to the phase III CONFIRM trial.
"We believe that based on the results of this study, treatment and practice should change. Patients should routinely receive the 500-mg dose," Dr. Angelo Di Leo declared in presenting the findings of CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) Dec. 10 at the San Antonio Breast Cancer Symposium.
CONFIRM was a randomized, double-blind, multicenter trial involving 736 postmenopausal women with estrogen receptor-positive advanced breast cancer. Their median age was 61 years, with a median 3.3 years since diagnosis of their malignancy. Nearly two-thirds had visceral involvement. All participants had prior therapy with an aromatase inhibitor or an antiestrogen hormonal treatment.
Patients were randomized to fulvestrant on the approved schedule of a 250-mg intramuscular injection on days 0, 14, 28, and monthly thereafter, or to two 250-mg injections on the same schedule. Patients on the standard dosing regimen also got a placebo intramuscular injection at the same time. (Technical limitations in the ability to concentrate the drug make it impossible to deliver more than 250 mg per injection.)
The primary end point in CONFIRM was time to disease progression from the start of fulvestrant therapy. It was a median of 6.5 months in the high-dose group, for a highly significant 20% improvement over the 5.5 months in the standard-dose group (P = .006), reported Dr. Di Leo, director of oncology at the Hospital of Prato (Italy).
The improvement in time to progression resulted from a combination of an increased clinical benefit rate (defined as complete or partial response or stable disease lasting at least 24 weeks) and longer duration of disease stabilization. Clinical benefit was documented in 45.6% of the fulvestrant 500-mg group (median duration, 16.6 months), compared with a 39.6% clinical benefit rate (median duration, 13.9 months) with fulvestrant 250 mg. There was no difference in tumor-shrinkage rates between the two study arms, as reflected in objective response rates of 9%-10%.
Median overall survival at the point in the trial when half of all patients had died was 25.1 months in the high-dose fulvestrant group, compared with 22.8 months with standard dosing, a 16% relative risk reduction that fell short of significance (P = .09). Another analysis of overall survival is prespecified when 75% of participants have died, which is expected to be in mid-2011.
The incidence and severity of adverse effects were closely similar in the two study arms. The toxicity was far less than that typically seen with chemotherapy, which is the next step in patients with hormone receptor-positive metastatic breast cancer who don't respond to antiestrogen therapy, Dr. Di Leo noted. He stressed the relevance to patients of time to progression while on fulvestrant as a clinically meaningful end point. The most common adverse events associated with fulvestrant were GI disturbances (affecting 20% of patients in each study arm) and joint disorders (about 19%).
Time to progression was consistent across all prespecified subgroups. It didn't vary according to progesterone receptor status, patient age, visceral involvement, presence or absence of measurable disease, the last endocrine therapy given before fulvestrant use, or the response to prior endocrine therapy.
Nevertheless, the investigators have embarked on Trans-CONFIRM, a preplanned exploratory substudy involving detailed analysis of 150 archived primary tumor samples from CONFIRM participants. The hypothesis is that it will be possible to define (biologically or clinically) a subset of patients who are particularly likely to benefit from high-dose fulvestrant, and another subgroup unlikely to benefit from down-regulation of the estrogen receptor. The roughly one-half of patients with acquired - as opposed to intrinsic - resistance to fulvestrant are the ones who are unlikely to benefit from the antiestrogen, the oncologist explained.
Symposium president Dr. C. Kent Osborne said in an interview that CONFIRM leaves him convinced that 500 mg of fulvestrant is the optimal dose.
"It's a really expensive drug, though, and I don't know if insurers will pay for the second dose. That'll probably be the determining factor in how much impact this study has on clinical practice," said Dr. Osborne, director of the cancer center at Baylor College of Medicine, Houston.
He added that he'd really like to see fulvestrant at this more favorable dose undergo study as adjuvant therapy in women with early breast cancer. That could conceivably result in much larger benefits than those seen when the drug is used in the setting of metastatic disease.
Dr. Di Leo disclosed that he is on the advisory board of AstraZeneca, which supported the CONFIRM study. Dr. Osborne has no relevant financial interests.



FULVESTRANT IN POSTMENOPAUSAL WOMEN WITH METASTATIC
BREAST CANCER PROGRESSING ON PRIOR ENDOCRINE THERAPY –
UPDATED RESULTS FROM AN EXPANDED ACCESS PROGRAMME
Presented at the 5th European Breast Cancer Conference held March 21-25, 2006, in Nice, France
PDF LINK

CONCLUSIONS
Fulvestrant 250 mg is an endocrine agent with demonstrable efficacy and a favourable tolerability profile in patients with advanced breast cancer.
In this analysis, many patients experienced prolonged periods of response or SD during fulvestrant treatment, with the median duration
of CB being 68 weeks.
Fulvestrant offers clinicians a valuable new option for the treatment of postmenopausal women with advanced breast cancer progressing on prior
endocrine therapy.




Med Clin (Barc). 2009 Sep 19;133(10):371-4. Epub 2009 Apr 1.
[Fulvestrant in heavily pretreated postmenopausal women with advanced breast cancer]

[Article in Spanish]
MartÃ*nez MarÃ*n V, Muñoz MartÃ*n AJ, Viñuela Benéitez MC, GarcÃ*a Alfonso P, Alonso Muñoz A, Pérez Manga G.
Hospital General Universitario Gregorio Marañón, Madrid, España. virgimarin9@hotmail.com
BACKGROUND AND OBJECTIVE: Fulvestrant (Flv) is a pure antiestrogen without agonist activity. Flv is effective as second line treatment in postmenopausal women with advanced breast cancer after tamoxifen. MATERIAL AND METHOD: We performed a retrospective study of 36 consecutive postmenopausal women treated with Flv and advanced breast cancer progressing on prior therapies. 62,8% received Flv as third line treatment or more (all patients had previously received endocrine treatment for early or advanced breast cancer), 54,3% adjuvant chemotherapy and 67,5% received chemotherapy for metastatic disease. Our objective was to analyze the response rate, clinical benefit, time to progression (TTP) and toxicity profile. RESULTS: In our study 11,4% patients had partial responses (PR) and 22,9% had a stable disease (SD) >24 weeks. Clinical benefit rate (CB) [RP+RC+SD]: 31,4%. TTP: 4,2 months (CI 95%, 2,6-5,8), with a median follow-up of 8,9 months. Flv was well tolerated, 22,9% patients had adverse events, all grade I/II, and only 5,7% of women gave up the treatment. CONCLUSIONS: These data demonstrate that Flv is an effective and safe therapy for heavily pre-treated postmenopausal women with advanced breast cancer.

PMID: 19339025 [PubMed - in process]