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Androgen annihilation strategy prolongs rPFS in mCRPC
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
FROM GUCS 2021
Declines in PSA screening may account for rise in metastatic prostate cancers
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
FROM GUCS 2021
Combo disappoints in metastatic, castration-resistant prostate cancer
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
FROM GUCS 2021