ESMO Congress 2011

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.