ALSYMPCA Trial: Radium-223 Prolongs Life in Some Prostate Cancers

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.