2011 ASCO Annual Meeting

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – In Medicare patients with poor prognosis cancers, aggressive treatments were more likely to be pursued in the patients with the highest socioeconomic status, but the treatments did not result in better 2-year survival rates.

Among Medicare patients with lung, esophageal, and pancreatic cancers, Dr. Sandra L. Wong of the University of Michigan, Ann Arbor, found that patients who ranked in the highest of five socioeconomic categories were more likely to receive aggressive treatments across all three cancer groups. Yet, after researchers adjusted for risk factors, there was no difference in the 2-year survival rates for patients at the lowest and highest socioeconomic levels.

Primary cancers of the lung, esophagus, and pancreas account for more than 35% of all cancer deaths in the United States and a sizable share of cancer-related costs, Dr. Wong observed. Survival rates have not improved much for patients with these poor prognosis cancers, yet aggressive treatment has increased in this patient group.

Dr. Wong and her colleagues examined 1992-2005 data from the Surveillance Epidemiology and End Results (SEER) registry, which is linked to Medicare claims data, for fee-for-service patients over age 65 years. There were 68,167 patients with lung cancer, 4,350 with esophageal cancer, and 12,779 with pancreatic cancer. Cancer stage at diagnosis was similar for those in the highest and lowest socioeconomic groups. Patients were placed in one of five groups based on measures derived on the basis of wealth and income, education, employment, and zip code.

Patients in the lowest socioeconomic group were more likely to be black, to need urgent admission, and to be treated at nonteaching hospitals with low patient volumes. About 35% of patients in the lowest socioeconomic status had advanced disease at diagnosis, and they were more likely to receive no cancer-directed treatments, according to the results of the study.

For all three cancer types, patients in the highest socioeconomic group were more likely to receive radiation, surgery, and chemotherapy. For the lowest socioeconomic group of patients with lung cancer, radiation therapy was given to 44%, surgery to 13%, and chemotherapy to more than 35%. For the highest socioeconomic group, the respective rates were 50%, 19%, and 39%. No cancer-directed therapy was given to 44% of patients in the lowest socioeconomic group versus 37% of the highest socioeconomic group.

Where care was delivered mattered to lung cancer outcomes, she said. When hospitals were located in high socioeconomic areas, there was a modest difference in adjusted 2-year survival for lung cancer patients based on patient socioeconomic status, at 12% for lowest and 14% for highest. But when hospitals were located in low socioeconomic areas, adjusted 2-year survival was 8% for those in the lowest socioeconomic group and 3% for those in the highest socioeconomic group.

Dr. Wong reported having no relevant financial disclosures.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – Denosumab, a drug newly approved for prevention of skeletal-related adverse events in cancer patients with bone metastases from solid tumors, is not cost effective when compared with zoledronic acid in patients with breast or prostate cancers, according to a pair of pharmacoeconomic analyses.

A review of data from a key phase III trial in 2,046 patients with metastatic breast cancer found the cost per quality-adjusted life-year (QALY) gained with denosumab (Xgeva) was $643,726 when compared with zoledronic acid (Zometa), John A. Carter and his coinvestigators reported in a poster presented at the annual meeting of the American Society of Clinical Oncology (ASCO).

This ratio is far higher than the $50,000 to $100,000 that is considered to be good value for a medical intervention, they said.

A related study in castration-resistant prostate cancer metastatic to the bone found even more substantial cost differentials. The resultant cost per QALY for denosumab would be approximately $1.25 million in this setting, reported Sonya H. Snedecor, Ph.D., and her coauthors in the second poster.

In both studies, investigators attributed the high cost per QALY to the higher drug acquisition cost of denosumab combined with limited added prevention of skeletal-related events (SREs) and a lack of overall survival or disease progression benefits for denosumab vs. zoledronic acid.

"What we found [in the prostate cancer study] is that there were very little gains in quality-adjusted life-years with the use of denosumab – very, very minuscule, about five per thousandths of a year," senior author Marc Botteman said in an interview.

"So you spend $5,000 to get that five per thousandths of a year, and that leads to a cost-effectiveness ratio of $1.25 million, which is way, way, way higher than what people typically consider to be acceptable in general, or in oncology," said Mr. Botteman, cofounder and managing partner of Pharmerit North America, a health economics and outcomes research firm that conducted the analyses. Both studies were sponsored by Novartis, maker of zoledronic acid.

For the two studies, Pharmerit developed a Markov model based on trial data to estimate survival, QALYs, number and costs of skeletal-related events, and drug and administration costs. QALYs were estimated by assigning utilities to four health states: prior to skeletal-related event; the event; post-event; and death.

"Quality-adjusted life-years are a metric used by health economists to estimate the value of treatment in terms of clinical benefits. The index combines survival and quality of life during that survival," Mr. Botteman said.

Denosumab maker Amgen responded to a request for a response with an e-mailed statement that challenged the models’ use of event rates based on clinical trials rather than event rates observed in real-world clinical practice. Amgen also contended that the models underestimate the value of denosumab "by attributing lower costs to SREs than those seen in the real world," and it criticized the limited time frames used in the models.

"Economic models should extend far enough into the future to capture the major health and economic outcomes. By truncating the modeling time frame the value of preventing/delaying SREs will also be reduced," it said.

The statement also touted denosumab’s superiority in preventing SREs in patients with advanced solid tumors, and contended that this "could result in direct cost offsets due to reduced incidence of SREs and related medical costs."

"Amgen stands by the value of Xgeva for patients, health care providers, and payers," the statement concluded, citing denosumab’s safety profile, subcutaneous administration, and other attributes not covered by Pharmerit’s model.

The breast cancer poster used data from a phase III trial that contributed to the Food and Drug Administration’s decision in November 2010 to approve denusumab for the prevention of SREs in patients with bone metastases from solid tumors. The trial found denosumab to be superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer that had spread to the bone. Both drugs showed similar results in overall survival, disease progression, and serious adverse events (J. Clin. Onc. 2010;28:5132-39).

The poster reported the cost of a denusumab injection to be nearly twice that of zoledronic acid, at $1,650 vs. $887. Compared with the older drug, denosumab was found to result in fewer SREs and resultant costs, and slightly more QALYs. It was associated with higher drug-related costs, however.

As a result, total discounted costs were higher for denosumab by an addition of $6,884 per patient over the period of analysis. The cost per QALY gained was $644,000 when excluding SREs and $613,000 per QALY when including SREs, the authors wrote.

Discussing the poster at the ASCO meeting, Dr. Thomas J. Smith of the Massey Cancer Center at Virginia Commonwealth University, Richmond, said it "raises some significant concern about money-driven value in metastatic breast cancer treatment."

Dr. Smith said that the study raises questions about physicians’ ability to negotiate prices, and how to use these data in making decisions. "I can tell you that at most hospitals, most P&T [pharmacy and therapeutics] committees have wrestled exactly with this, ... and where does this fit in pathway-driven managed care, where you get a fixed amount to take care of these patients?" he said.

That the analysis was funded by the maker of zoledronic acid also was a concern. "So I would wait to draw conclusions until this has been through peer review," Dr. Smith said.

The prostate cancer study found that denosumab marginally improved quality of life (+0.0043 QALYs) relative to zoledronic acid, and reduced costs of SREs by $1,924 based on a calculation that these would cost $7,604 with denosumab vs. $9,528 with zoledronic acid over 27 months of treatment. To achieve those benefits, the patient would have to invest more than $7,313 in additional drug costs with denosumab, and thus incur a net cost of $5,390 over 27 months, according to the study.

Novartis, the maker of zoledronic acid, sponsored both studies. Mr. Carter and Dr. Snedecor disclosed consultant or advisory roles with Novartis. One of their coauthors was a Novartis employee with stock ownership. Mr. Botteman disclosed consultant or advisory roles with Pharmerit. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.

CHICAGO – The combination of busulfan and melphalan is superior to the combination of carboplatin, etoposide, and melphalan when used as myeloablative therapy in children with high-risk neuroblastoma, new data show.

In a randomized trial conducted by the SIOPEN (International Society of Pediatric Oncology European Neuroblastoma) Group among 563 such patients, busulfan plus melphalan yielded higher 3-year rates of event-free survival (49% vs. 33%; P less than .001) and overall survival (60% vs. 48%; P = .003), investigators reported in the plenary session at the annual meeting of the American Society of Clinical Oncology.

It had a better toxicity profile overall as well. The main adverse effect of busulfan plus melphalan (BUMEL), as expected, was veno-occlusive disease, but only 5% of patients experienced a grade 3 occlusive event.

"This is the first time that in pediatric oncology that we can clearly demonstrate that the choice of the myeloablative therapy really matters," said principal investigator Dr. Ruth Ladenstein of the St. Anna Children’s Hospital and Research Institute in Vienna.

"Summing up all the results, we feel that current practice should now be in favor of busulfan-melphalan in high-risk neuroblastoma," she said.

Discussant Dr. Julie R. Park called the SIOPEN trial "a great achievement in pediatric clinical research," noting, for example, its collaborative nature and completion despite the use of two toxic myeloablative regimens.

Yet, she cautioned, the event-free survival rate of 33% for the CEM (carboplatin, etoposide, and melphalan) regimen was much lower than that observed in the previous COG (Children’s Oncology Group) A3973 trial of this regimen (46%), possibly because of different treatment strategies and patient populations, and dose-reductions of CEM for renal toxicity in the new trial.

"The SIOPEN trial does demonstrate that the busulfan-melphalan regimen is superior to carboplatin, etoposide, and melphalan in the context of receiving rapid COJEC [cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide] induction and in a cohort of patients with good response to induction therapy," said Dr. Park, chair of COG’s Neuroblastoma Scientific Committee and a pediatric oncologist at the University of Washington in Seattle. "The COG data indicate that these results may not be applicable to those children who have received the N6 Memorial Sloan-Kettering induction" regimen.

"The toxicities of busulfan-melphalan, primarily veno-occlusive disease, will need to be taken into account as we consider whether further modifications of consolidation therapy can occur," she added.

Perhaps of greater importance, the majority of the SIOPEN trial’s initially eligible patients were unable to undergo randomization because of an inadequate response to induction therapy, as has been seen on other trials.

"Future high-risk neuroblastoma trials must address the need for improved induction response, as poor induction remains a major barrier to our cure of these children," Dr. Park asserted. "And continued improvement of postconsolidation [therapy] needs to be studied, as that has shown our maximal success in treating these children."

The trial was the first high-risk neuroblastoma trial (HR-NBL1) undertaken by SIOPEN. The design called for rapid COJEC induction followed by peripheral stem cell harvest, a first round of local control (attempted complete surgery of the primary tumor), randomized myeloablative therapy with stem cell rescue, a second round of local control (radiation therapy to the primary tumor), and finally maintenance therapy.

Patients could proceed to randomized myeloablative therapy only if they had an adequate response of metastases to the rapid induction regimen and had an adequate number of stem cells harvested.

They were randomized to BUMEL or CEM. The busulfan was given orally until 2006, after which an intravenous form became available.

A preplanned interim analysis showed efficacy in favor of BUMEL, Dr. Ladenstein reported. The trial was therefore stopped early, after a median observation period of 3.5 years. The 563 randomized patients (just 43% of those initially enrolled) had a median age of 3 years. In all, 83% had stage IV disease.

Presenting the main efficacy results, she said "we find [them] quite extraordinary and above our expectations."

"Most interestingly, this really was related to a decreased relapse rate under the busulfan-melphalan regimen and was not related to [decreased] transplant-related mortality," she noted.

Stratified analyses suggested that BUMEL had the greatest benefit in patients who had residual disease after induction. "We believe that this is related to the potency of the drugs to work on the resting tumor cells," Dr. Ladenstein commented.

In a multivariate analysis that included age, disease stage, and treatment group, patients still had a significantly reduced risk of events if they were assigned to BUMEL instead of CEM (hazard ratio, 0.64; P less than .001).

CEM was associated with higher rates of grade 3/4 infectious, gastrointestinal, and renal adverse effects, and ototoxicity. BUMEL was associated with a higher rate of grade 3/4 veno-occlusive disease; patients in the trial did not receive prophylactic anticoagulation with defibrotide, she noted.

Dr. Ladenstein and Dr. Park said they had no disclosures. The intravenous form of busulfan was provided by Pierre Fabre Médicament Oncology.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.