HER2 Support Group Forums - View Single Post

Rich66 · 08-13-2009, 01:06 PM

FDA Approves New Dosing for Fulvestrant in Treatment of Metastatic Breast Cancer in HR+ Postmenopausal Women

WILMINGTON, Del -- September 10, 2010 -- The US Food and Drug Administration (FDA) has approved the 500-mg dose of fulvestrant (FASLODEX Injection), replacing the previously approved monthly dose of fulvestrant 250 mg, for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following anti-oestrogen therapy.

The FDA approval of fulvestrant 500 mg was based on results from the phase 3 Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) study, which demonstrated that fulvestrant 500 mg significantly reduced the risk of disease progression in patients with metastatic breast cancer, when compared with the 250-mg dose. Safety and tolerability profiles of both doses were comparable.

The CONFIRM study, presented for the first time at the annual San Antonio Breast Cancer Symposium in December 2009, showed fulvestrant 500 mg reduced the risk of disease progression (assessed as progression-free survival) by 20% (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.68-0.94; P = .006) when compared with fulvestrant 250 mg. Fulvestrant 500 mg significantly increased median progression-free survival to 6.5 versus 5.4 months with 250 mg (P = .006).

Objective response rates calculated in patients with measurable disease were not significantly different between fulvestrant 500 mg (13.8%) and 250 mg (14.6%) (HR = 0.94; 95% CI, 0.57-1.55; P = .795). Median overall survival was 25.1 months with fulvestrant 500 mg and 22.8 months with fulvestrant 250 mg (HR = 0.84; 95% CI, 0.69-1.03; P = .091). At the time of analysis, overall survival was not statistically significant. A preplanned second survival analysis will occur as data mature when approximately 75% of patients have had an event.

The recommended dose of fulvestrant 500 mg should be administered intramuscularly into the buttocks as two 250-mg injections, one in each buttock, on days 1, 15, 29, and once monthly thereafter. A dose of 250 mg is recommended in patients with moderate hepatic impairment.

Fulvestrant 500 mg will be supplied as 2 x 250 mg/5 mL packaged together in early fourth quarter 2010. During this time, fulvestrant 250 mg will still be available.

SOURCE: AstraZeneca

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

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. Sk

odowskiej-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 antiestrogenfulvestrant at 500 mg/mo (double the approved dose) with thearomatase inhibitor anastrozole as first-line endocrine therapyfor advanced hormone receptor–positive breast cancer inpostmenopausal women.
Patients and Methods: FIRST (FulvestrantFirst-Line Study Comparing Endocrine Treatments) is a phaseII, randomized, open-label, multicenter study of a fulvestranthigh-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month1) versus anastrozole (1 mg/d). The primary efficacy end pointwas clinical benefit rate (CBR), defined as the proportion ofpatients experiencing an objective response (OR) or stable diseasefor

24 weeks. The primary analysis was performed 6 months afterthe last patient was randomly assigned.
Results: CBR was similarfor 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 betweentreatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Timeto progression (TTP) was significantly longer for fulvestrantversus anastrozole (median TTP not reached for fulvestrant HDv 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39to 1.00; P = .0496). Duration of OR and CB also numericallyfavored fulvestrant HD. Both treatments were well tolerated,with no significant differences in the incidence of prespecifiedadverse events.
Conclusion: First-line fulvestrant HD was atleast as effective as anastrozole for CBR and ORR and was associatedwith significantly longer TTP. Fulvestrant HD was generallywell tolerated, with a safety profile similar to that of anastrozole.

Breast. 2008 Apr;17 Suppl 3:S16-21. Epub 2008 Mar 18.

Links

Fulvestrant: expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer.

Chia S, Gradishar W.
Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. SChia@bccancer.bc.ca
With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptor-positive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (Faslodex) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment.
PMID: 18353647 [PubMed - indexed for MEDLINE]

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.

Breast Cancer Res Treat. 2010 Sep;123(2):453-61. Epub 2010 Jul 15.
Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2).

Pritchard KI, Rolski J, Papai Z, Mauriac L, Cardoso F, Chang J, Panasci L, Ianuli C, Kahan Z, Fukase K, Lindemann JP, Macpherson MP, Neven P.
Sunnybrook Odette Cancer Centre and University of Toronto, 2075 Bayview Avenue, M4N 3M5, Toronto, ON, Canada. kathy.pritchard@sunnybrook.ca

LINK

Abstract

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

PMID: 20632084 [PubMed - in process]

08-13-2009, 01:06 PM	#3
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Fulvestrant+chemo synergy FDA Approves New Dosing for Fulvestrant in Treatment of Metastatic Breast Cancer in HR+ Postmenopausal Women WILMINGTON, Del -- September 10, 2010 -- The US Food and Drug Administration (FDA) has approved the 500-mg dose of fulvestrant (FASLODEX Injection), replacing the previously approved monthly dose of fulvestrant 250 mg, for the treatment of hormone receptor-positive (HR+) metastatic breast cancer in postmenopausal women with disease progression following anti-oestrogen therapy. The FDA approval of fulvestrant 500 mg was based on results from the phase 3 Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) study, which demonstrated that fulvestrant 500 mg significantly reduced the risk of disease progression in patients with metastatic breast cancer, when compared with the 250-mg dose. Safety and tolerability profiles of both doses were comparable. The CONFIRM study, presented for the first time at the annual San Antonio Breast Cancer Symposium in December 2009, showed fulvestrant 500 mg reduced the risk of disease progression (assessed as progression-free survival) by 20% (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.68-0.94; P = .006) when compared with fulvestrant 250 mg. Fulvestrant 500 mg significantly increased median progression-free survival to 6.5 versus 5.4 months with 250 mg (P = .006). Objective response rates calculated in patients with measurable disease were not significantly different between fulvestrant 500 mg (13.8%) and 250 mg (14.6%) (HR = 0.94; 95% CI, 0.57-1.55; P = .795). Median overall survival was 25.1 months with fulvestrant 500 mg and 22.8 months with fulvestrant 250 mg (HR = 0.84; 95% CI, 0.69-1.03; P = .091). At the time of analysis, overall survival was not statistically significant. A preplanned second survival analysis will occur as data mature when approximately 75% of patients have had an event. The recommended dose of fulvestrant 500 mg should be administered intramuscularly into the buttocks as two 250-mg injections, one in each buttock, on days 1, 15, 29, and once monthly thereafter. A dose of 250 mg is recommended in patients with moderate hepatic impairment. Fulvestrant 500 mg will be supplied as 2 x 250 mg/5 mL packaged together in early fourth quarter 2010. During this time, fulvestrant 250 mg will still be available. SOURCE: AstraZeneca High dose Fulvestrant more effective than anastrozol for 1st line mets 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 antiestrogenfulvestrant at 500 mg/mo (double the approved dose) with thearomatase inhibitor anastrozole as first-line endocrine therapyfor advanced hormone receptor–positive breast cancer inpostmenopausal women. Patients and Methods: FIRST (FulvestrantFirst-Line Study Comparing Endocrine Treatments) is a phaseII, randomized, open-label, multicenter study of a fulvestranthigh-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month1) versus anastrozole (1 mg/d). The primary efficacy end pointwas clinical benefit rate (CBR), defined as the proportion ofpatients experiencing an objective response (OR) or stable diseasefor 24 weeks. The primary analysis was performed 6 months afterthe last patient was randomly assigned. Results: CBR was similarfor 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 betweentreatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Timeto progression (TTP) was significantly longer for fulvestrantversus anastrozole (median TTP not reached for fulvestrant HDv 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39to 1.00; P = .0496). Duration of OR and CB also numericallyfavored fulvestrant HD. Both treatments were well tolerated,with no significant differences in the incidence of prespecifiedadverse events. Conclusion: First-line fulvestrant HD was atleast as effective as anastrozole for CBR and ORR and was associatedwith significantly longer TTP. Fulvestrant HD was generallywell tolerated, with a safety profile similar to that of anastrozole. Breast. 2008 Apr;17 Suppl 3:S16-21. Epub 2008 Mar 18. Links Fulvestrant: expanding the endocrine treatment options for patients with hormone receptor-positive advanced breast cancer. Chia S, Gradishar W. Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. SChia@bccancer.bc.ca With the aromatase inhibitors (AIs) replacing tamoxifen as the first-line treatment for postmenopausal women with hormone receptor-positive early and advanced breast cancer, there is a need to evaluate appropriate endocrine treatment options following AI failure. However, until recently, there were no Phase III trial data in this area. Fulvestrant (Faslodex) is an oestrogen receptor antagonist utilised for the treatment of postmenopausal women with locally advanced or metastatic breast cancer following progression or recurrence on anti-oestrogen therapy. Fulvestrant has a mode of action that is distinct from the AIs and the selective oestrogen receptor modulators, and thus may offer an effective treatment option in the post-AI setting. The Evaluation of Faslodex and Exemestane Clinical Trial (EFECT) is the first Phase III trial to evaluate the efficacy and tolerability of fulvestrant and the steroidal AI, exemestane, in patients with locally advanced or metastatic breast cancer who have progressed or recurred while receiving a non-steroidal AI. EFECT confirmed that fulvestrant and exemestane offer effective treatment options in this setting. Similar efficacy was seen in both treatment groups and there were no significant differences in reported adverse events between fulvestrant and exemestane. The EFECT data provide further evidence for the activity of fulvestrant in the treatment of advanced breast cancer. Other ongoing fulvestrant trials will further define its full role, including the potential for a high-dose regimen, combination of fulvestrant with an AI, and identification of clinical and biological markers to help in targeting those patients who are most likely to respond to treatment. PMID: 18353647 [PubMed - indexed for MEDLINE] 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. Breast Cancer Res Treat. 2010 Sep;123(2):453-61. Epub 2010 Jul 15. Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2). Pritchard KI, Rolski J, Papai Z, Mauriac L, Cardoso F, Chang J, Panasci L, Ianuli C, Kahan Z, Fukase K, Lindemann JP, Macpherson MP, Neven P. Sunnybrook Odette Cancer Centre and University of Toronto, 2075 Bayview Avenue, M4N 3M5, Toronto, ON, Canada. kathy.pritchard@sunnybrook.ca LINK Abstract The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients. PMID: 20632084 [PubMed - in process]