Longer-term safety of radium-223 is reassuring

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.