May 25, 2011 — Abiraterone acetate (Zytiga, Cougar Biotechnology), which was approved in the United States just last month, is the latest of several new treatment options available for advanced prostate cancer.
The study that led to the approval and that shows that abiraterone significantly prolongs overall survival in men with metastatic castration-resistant prostate cancer who have received chemotherapy has now been published in the May 26 issue of the New England Journal of Medicine.
The data from this pivotal 1195-patient trial of the new agent were first reported at the 2010 European Society for Medical Oncology Congress.
Median overall survival in patients randomized to abiraterone plus prednisone was 14.8 months; in those randomized to placebo plus prednisone, it was 10.9 months (hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P < .001).
Notably, the trial's data monitoring committee recommended unblinding the study to allow the placebo group to switch to abiraterone because of the survival benefit.
The study's secondary end points also favored the treatment group, and were all statistically significant, including time to prostate-specific antigen (PSA) progression (10.2 vs 6.6 months; P < .001), progression-free survival (5.6 vs 3.6 months; P < .001), and PSA response rate (29% vs 6%; P < .001), report the authors, led by Johann de Bono, MBBS, PhD, from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust in London, United Kingdom.
Abiraterone represents a first in the treatment of men whose disease has progressed while on androgen-deprivation therapy, said senior author Howard I. Scher, MD.
"This trial establishes a new category of treatment for men who have progressed on conventional hormone therapies, as well as chemotherapy. It proves that these previously treated patients have tumors that are still hormonally responsive. Previously, this was the point in the illness where hormonal agents were typically not considered," said Dr. Scher, from Memorial Sloan-Kettering Cancer Center in New York City, in a press statement.
Not Just a Second-Line Therapy?
The study findings "provide a proof of principle that metastatic castration-resistant prostate cancer remains androgen-driven," according to an editorial that accompanies the study.
Abiraterone is an inhibitor of androgen biosynthesis, note editorialists Emmanuel S. Antonarakis, MD, and Mario A. Eisenberger, MD, from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
They believe that the new agent should not be limited to second-line use.
"These results provide sufficient evidence of efficacy to justify the use of abiraterone in all patients with metastatic castration-resistant prostate cancer (i.e., even those with no previous chemotherapy treatment)," they write.
Dr. Antonarakis and Dr. Eisenberger point out that the treatment landscape in this setting has changed a great deal recently.
In 2010, 2 new therapies were approved by the US Food and Drug Administration for men with metastatic castration-resistant prostate cancer: the immunotherapy sipuleucel-T (a first-line treatment indicated for men with minimal or no symptoms), and the chemotherapy cabazitaxel (second-line treatment indicated for men with disease progression after docetaxel treatment).
At this year's annual meeting of the National Comprehensive Cancer Network, the chair of the organization's prostate cancer panel, in describing all of these changes, said that treatment in this setting has been "completely revamped."
But which agent should come first and in what combination? That is a question without an answer right now, the editorialists explain.
"Data are lacking to define the optimal sequence and combination of abiraterone with other agents, to determine the activity and toxicity of other androgen-receptor-targeting drugs (e.g., MDV3100) . . . and to integrate androgen-receptor-directed therapies with other therapies," the write.
Adverse Events Were "Easily Manageable"
In this study, Dr. de Bono and colleagues at 147 centers in 13 countries randomly assigned 1195 patients with castration-resistant metastatic prostate cancer, who had been previously treated with docetaxel, to either abiraterone 1000 mg plus prednisone 5 mg twice daily (n = 797) or placebo plus prednisone (n = 398).
The authors report that toxic effects were predominantly grade 1 or 2, and that there were low rates of drug discontinuation and dose reduction.
However, adverse events were more commonly observed in the abiraterone group. Toxic effects "were largely mechanism-based," say the authors. Among these were (for all grades, comparing treatment with placebo) fluid retention (31% vs 22%) and hypokalemia (17% vs 8%). However, grade 3/4 hypokalemia (3.8% vs 0.8%) and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent.
The effects were "largely abrogated by the use of low-dose prednisone or prednisolone (5 mg twice a day), similar to the mitigation of hypertension and hypokalemia observed with the use of corticosteroids in the well-characterized syndrome of congenital CYP17 deficiency," note the authors.
Treatment with abiraterone did not appear to increase the risk for metabolic changes or symptoms associated with chronic androgen deprivation, such as diabetes and loss of musculature. "Nevertheless, longer follow-up is warranted to evaluate late toxic effects," write the authors.
The adverse effects were "easily manageable and reversible, despite the advanced age and level of frailty of the study population," conclude the authors.
However, they had some additional qualifying comments about one adverse event — the elevated liver enzymes levels seen with the new therapy. Grade 4 elevations in aminotransferase levels were observed early in the study, they say, but no additional cases were observed after a protocol amendment, which mandated more frequent monitoring with liver function tests during the first 12 weeks. The amendment called for treatment to be suspended in the event of grade 3 elevations in serum aminotransferase levels; abiraterone was reintroduced at a reduced dose when liver enzyme levels returned to baseline values, they say.
N Engl J Med. 2011;364:1995-2005 and 2055-2058.
The study that led to the approval and that shows that abiraterone significantly prolongs overall survival in men with metastatic castration-resistant prostate cancer who have received chemotherapy has now been published in the May 26 issue of the New England Journal of Medicine.
The data from this pivotal 1195-patient trial of the new agent were first reported at the 2010 European Society for Medical Oncology Congress.
Median overall survival in patients randomized to abiraterone plus prednisone was 14.8 months; in those randomized to placebo plus prednisone, it was 10.9 months (hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P < .001).
Notably, the trial's data monitoring committee recommended unblinding the study to allow the placebo group to switch to abiraterone because of the survival benefit.
The study's secondary end points also favored the treatment group, and were all statistically significant, including time to prostate-specific antigen (PSA) progression (10.2 vs 6.6 months; P < .001), progression-free survival (5.6 vs 3.6 months; P < .001), and PSA response rate (29% vs 6%; P < .001), report the authors, led by Johann de Bono, MBBS, PhD, from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust in London, United Kingdom.
Abiraterone represents a first in the treatment of men whose disease has progressed while on androgen-deprivation therapy, said senior author Howard I. Scher, MD.
"This trial establishes a new category of treatment for men who have progressed on conventional hormone therapies, as well as chemotherapy. It proves that these previously treated patients have tumors that are still hormonally responsive. Previously, this was the point in the illness where hormonal agents were typically not considered," said Dr. Scher, from Memorial Sloan-Kettering Cancer Center in New York City, in a press statement.
Not Just a Second-Line Therapy?
The study findings "provide a proof of principle that metastatic castration-resistant prostate cancer remains androgen-driven," according to an editorial that accompanies the study.
Abiraterone is an inhibitor of androgen biosynthesis, note editorialists Emmanuel S. Antonarakis, MD, and Mario A. Eisenberger, MD, from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
They believe that the new agent should not be limited to second-line use.
"These results provide sufficient evidence of efficacy to justify the use of abiraterone in all patients with metastatic castration-resistant prostate cancer (i.e., even those with no previous chemotherapy treatment)," they write.
Dr. Antonarakis and Dr. Eisenberger point out that the treatment landscape in this setting has changed a great deal recently.
In 2010, 2 new therapies were approved by the US Food and Drug Administration for men with metastatic castration-resistant prostate cancer: the immunotherapy sipuleucel-T (a first-line treatment indicated for men with minimal or no symptoms), and the chemotherapy cabazitaxel (second-line treatment indicated for men with disease progression after docetaxel treatment).
At this year's annual meeting of the National Comprehensive Cancer Network, the chair of the organization's prostate cancer panel, in describing all of these changes, said that treatment in this setting has been "completely revamped."
But which agent should come first and in what combination? That is a question without an answer right now, the editorialists explain.
"Data are lacking to define the optimal sequence and combination of abiraterone with other agents, to determine the activity and toxicity of other androgen-receptor-targeting drugs (e.g., MDV3100) . . . and to integrate androgen-receptor-directed therapies with other therapies," the write.
Adverse Events Were "Easily Manageable"
In this study, Dr. de Bono and colleagues at 147 centers in 13 countries randomly assigned 1195 patients with castration-resistant metastatic prostate cancer, who had been previously treated with docetaxel, to either abiraterone 1000 mg plus prednisone 5 mg twice daily (n = 797) or placebo plus prednisone (n = 398).
The authors report that toxic effects were predominantly grade 1 or 2, and that there were low rates of drug discontinuation and dose reduction.
However, adverse events were more commonly observed in the abiraterone group. Toxic effects "were largely mechanism-based," say the authors. Among these were (for all grades, comparing treatment with placebo) fluid retention (31% vs 22%) and hypokalemia (17% vs 8%). However, grade 3/4 hypokalemia (3.8% vs 0.8%) and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent.
The effects were "largely abrogated by the use of low-dose prednisone or prednisolone (5 mg twice a day), similar to the mitigation of hypertension and hypokalemia observed with the use of corticosteroids in the well-characterized syndrome of congenital CYP17 deficiency," note the authors.
Treatment with abiraterone did not appear to increase the risk for metabolic changes or symptoms associated with chronic androgen deprivation, such as diabetes and loss of musculature. "Nevertheless, longer follow-up is warranted to evaluate late toxic effects," write the authors.
The adverse effects were "easily manageable and reversible, despite the advanced age and level of frailty of the study population," conclude the authors.
However, they had some additional qualifying comments about one adverse event — the elevated liver enzymes levels seen with the new therapy. Grade 4 elevations in aminotransferase levels were observed early in the study, they say, but no additional cases were observed after a protocol amendment, which mandated more frequent monitoring with liver function tests during the first 12 weeks. The amendment called for treatment to be suspended in the event of grade 3 elevations in serum aminotransferase levels; abiraterone was reintroduced at a reduced dose when liver enzyme levels returned to baseline values, they say.
N Engl J Med. 2011;364:1995-2005 and 2055-2058.
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