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CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.
The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).
"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.
The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).
Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.
Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.
"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."
Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.
The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*
Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.
"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.
"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.
The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.
Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.
Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.
In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.
If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.
Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."
While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.
"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.
"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"
The investigators disclosed numerous relationships with pharmaceutical companies.
* This story was updated with additional analysis from Dr. Oh on 6/6/2012.
CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.
The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).
"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.
The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).
Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.
Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.
"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."
Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.
The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*
Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.
"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.
"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.
The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.
Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.
Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.
In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.
If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.
Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."
While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.
"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.
"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"
The investigators disclosed numerous relationships with pharmaceutical companies.
* This story was updated with additional analysis from Dr. Oh on 6/6/2012.
CHICAGO – Enjoying periodic breaks from hormonal therapy can take years off the life of a man with metastatic prostate cancer, according to results of the largest and longest clinical trial comparing intermittent androgen deprivation with continuous therapy.
The data are expected to squelch the use of intermittent androgen therapy (IAD) in men seeking quality-of-life improvements without reducing the efficacy of treatment for advanced disease. Previous studies suggested no harm would be done, but up to now physicians did not have a definitive comparison with continuous androgen deprivation (CAD).
"This study for the first time demonstrates that there is a price to pay, and in the patients most likely to receive intermittent therapy in this country and around the world, the minimal disease patients, it is almost 2 years’ median survival. So I think that is an important fact," said Dr. Bruce J. Roth, moderator of a press briefing at the American Society of Clinical Oncology annual meeting, where the outcomes were presented in a plenary session on Sunday, June 3.
The greatest impact was seen in men with minimal disease, who lived a median of 5.2 years if randomized to intermittent therapy vs. 7.1 years with continuous treatment, according to Dr. Maha Hussain, the lead author. Half of the men in the continuous arm, but only 42% on intermittent therapy, were alive at 7 years in the phase III intergroup study led by the Southwest Oncology Group (SWOG).
Men with extensive disease fared no worse on IAD – their median overall survival reached 5 years vs. 4.4 years among those on CAD. The investigators found this "striking and surprising because it goes against conventional belief based on all the trials that have been done thus far with this disease," said Dr. Hussain, a professor of medicine and urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. A third of these men were alive at 7 years, regardless of which regimen they received.
Overall, IAD did not meet the standard of non-inferiority to CAD, Dr. Hussain emphasized. At a median 9.2 years of follow-up, men randomized to CAD lived a median of 5.8 years vs. 5.1 years with IAD.
"Because of these findings continuous therapy continues to be the standard of care," said Dr. Hussain; IAD was not inferior to CAD in patients with extensive disease, but it was "significantly inferior" in men with minimal disease. "These observations suggest inherent biological differences and warrant further evaluations."
Asked whether she might recommend IAD in men with extensive disease, she cautioned that the data in this group came from a secondary analysis and are not understood. Moreover, many new therapies are emerging, giving more options to men with metastatic prostate cancer.
The trial used a nonstandard definition of extensive disease and the subset analysis was not "preplanned," Dr. William K. Oh said, dismissing the extensive disease finding in a plenary session discussion of the presentation.*
Overall, he called the trial a "Herculean effort" and noted that, unlike many previous studies, it was adequately powered to determine overall survival. Preclinical mouse studies that suggested IAD might delay time to castration resistance should no longer be cited as a rationale for IAD, he added.
"Neither this nor any randomized trial has ever shown a superior outcome with intermittent ADT [androgen deprivation therapy]," said Dr. Oh, chief of the Division of Hematology and Medical Oncology at Mt. Sinai Medical Center in New York.
"Continuous ADT remains the standard of care for all patients with metastatic prostate cancer," he concluded, allowing that it might still be considered in patients with nonmetastatic rising PSA.
The trial was started in 1995; at that time median survival was 2.5 – 3 years, and physicians hoped that intermittent therapy could relieve side effects impinging on quality of life. Based on experimental data, investigators hypothesized that delivering less drug over time might delay resistance to hormonal therapy. The non-inferiority trial design required that the investigators could rule out a 20% or greater relative increase in risk of death with a 95% confidence interval.
Dr. Hussain, Dr. Roth, and Dr. Oh offered a number of reasons why the non-inferiority trial revealed a negative impact that was not seen in the previous studies.
Notably, the SWOG 9346 (Intergroup -0162) trial was larger, involving 5 cancer research groups in the United States, Canada, and Europe. They accrued 3,040 patients with newly diagnosed metastatic prostate cancer and a PSA of at least 5 by 2008.
In addition, the trial randomized only men with newly metastatic disease who had achieved a PSA of 4.0 or less after 7 months of CAD with goserelin and bicalutamide – starting 770 patients on IAD and continuing 759 patients to CAD. The median age was 70, about half (48%) had extensive disease, and 14% were African Americans. Men on IAD were monitored monthly and went back on therapy based on predetermined parameters.
If PSA rose to 20 ng/ml in men on IAD or to a pre-registration baseline below 20 ng/ml, therapy was restarted; it could also be restarted based on symptoms. After 7 months, men could take another break if their PSA normalized. An increase to greater than 4 ng/ml on months 6 or 7 would send them back to continuous therapy until progression.
Previous studies enrolled populations with earlier stage disease before physicians could determine whether they were responsive to hormone therapy or not, noted Dr. Roth, professor of medicine in the division of oncology at Washington University School of Medicine. The men in this trial "were the most likely to benefit from hormone therapy."
While the number of men trying IAD is not known, it is used in the United States, Dr. Roth said. He does not offer it to his patients – and will not offer it going forward – but often sees it in the charts of patients referred to him.
"A 2-year difference in median survival is huge," he said, predicting patients would not press for IAD once they discussed the research with their physicians.
"Are you going to trade off hot flashes for a 2-year decrease in median overall survival with IAD?" he proposed asking a patient. "I think the average patient will say, ‘Those hot flashes are not so bad.’"
The investigators disclosed numerous relationships with pharmaceutical companies.
* This story was updated with additional analysis from Dr. Oh on 6/6/2012.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Major Finding: Men with minimal disease lived a median of 5.2 years if randomized to intermittent androgen deprivation vs. 7.1 years with continuous androgen deprivation.
Data Source: Data are based on more than 1,500 men with hormone-sensitive metastatic prostate cancer in the randomized, phase III Southwest Oncology Group 9346 trial.
Disclosures: The investigators disclosed numerous relationships with pharmaceutical companies.