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CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.
The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.
Subsequent therapy may mask a survival benefit
In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.
A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.
Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”
In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.
Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.
“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”
Analysis confirms efficacy, safety in heavily pretreated patients
In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.
In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.
Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.
The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.
“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”
She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.
Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.
“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”
Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.
She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.
Models suggest maintenance therapy is not cost-effective
In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.
They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.
In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.
Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.
Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.
“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.
“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.
CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.
The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.
Subsequent therapy may mask a survival benefit
In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.
A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.
Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”
In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.
Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.
“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”
Analysis confirms efficacy, safety in heavily pretreated patients
In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.
In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.
Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.
The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.
“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”
She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.
Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.
“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”
Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.
She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.
Models suggest maintenance therapy is not cost-effective
In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.
They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.
In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.
Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.
Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.
“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.
“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.
CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.
The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.
Subsequent therapy may mask a survival benefit
In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.
A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.
Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”
In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.
Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.
“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”
Analysis confirms efficacy, safety in heavily pretreated patients
In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.
In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.
Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.
The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.
“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”
She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.
Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.
“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”
Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.
She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.
Models suggest maintenance therapy is not cost-effective
In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.
They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.
In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.
Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.
Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.
“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.
“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
