In the United States, cancer is ranked second among the most expensive diseases to treat.1 With an increasing proportion of cost incurred to patients as direct out-of-pocket copayments or shared-payment plans, cancer patients are especially at risk of experiencing financial toxicity, resulting in a lower quality of life, further limiting access to the highest quality care, and increasingly leading to personal bankruptcy. Cost-effectiveness analyses to compare the relative value of treatment are urgently needed owing to the recent proliferation of expensive and heavily marketed novel therapies. Advanced ovarian cancer is initially treated by a sequence of surgery and chemotherapy with a high likelihood of achieving disease remission, but with 80–90% rates of eventual relapse. Although broadly considered incurable at the time of recurrence, patients may enter a second or third remission with successful therapy. Medically prolonging the time in remission has been an area of active research. Poly (ADP-ribose) polymerase inhibitors are a relatively recent U.S. Food and Drug Administration (FDA)–approved class of drug approved as maintenance therapy in recurrent ovarian cancer. Although the three available poly (ADP-ribose) polymerase inhibitors (olaparib, niraparib, rucaparib) are selectively targeted to be clinically most effective in patients with a germline BRCA mutation or those having a tumor with homologous recombination deficiency, they were approved as maintenance treatments without restriction by biomarker.2 The financial consequences of maintenance treatment are significant as patients may receive months to years of daily therapy. The cost-effectiveness literature to date has been limited to olaparib, and has not included homologous recombination deficiency testing as a means of selecting patients where the relative value of poly (ADP-ribose) polymerase inhibitor may be higher.3,4
Widespread poly (ADP-ribose) polymerase inhibitor use as maintenance therapy in all patients with recurrent, platinum-sensitive ovarian cancer has the potential to dramatically escalate U.S. health care costs. Given the known differences in reported effectiveness in biomarker-identified subgroups, this study aims to determine the cost effectiveness of maintenance poly (ADP-ribose) polymerase inhibitor using a decision analysis model of four different strategies to examine the implications of the broader FDA labeling compared with biomarker-driven use of poly (ADP-ribose) polymerase inhibitor.
A decision analysis model was created to compare the cost effectiveness of four strategies for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using a societal perspective: 1) observation; 2) BRCA germline mutation testing, followed by selective treatment of only those patients with germline BRCA mutations with maintenance poly (ADP-ribose) polymerase inhibitor (“gBRCA only”); 3) both BRCA germline mutation testing and tumor HRD testing, followed by selective treatment of only those patients with either BRCA germline mutations or those with homologous recombination deficiency positive tumors with maintenance poly (ADP-ribose) polymerase inhibitor (“gBRCA and homologous recombination deficiency only”); and 4) treatment of all patients with maintenance poly (ADP-ribose) polymerase inhibitor (“treat all”). The population of interest was those patients eligible for maintenance poly (ADP-ribose) polymerase inhibitor therapy according to FDA labeling, the estimated 5,570 cases of ovarian cancer patients with platinum-sensitive recurrences in 2017 in the United States.4,5 Strategies were compared using incremental cost-effectiveness ratios, defined as the ratio of the difference in costs between strategies and the difference in quality-adjusted progression-free survival between strategies.
Models were generated and analysis was programmed using TreeAge Pro 2017 software. The MD Anderson Cancer Center institutional review board reviewed and exempted this study from the approval process after determination that it is not human subjects research.
For our model's base case, we primarily used the supporting data from the first FDA maintenance approval in poly (ADP-ribose) polymerase inhibitor, the NOVA study, a randomized, double-blind, phase three trial of 553 patients with platinum-sensitive recurrent ovarian cancer randomized to niraparib or placebo.6 The median age ranged between 57 and 63, and most patients had stages III or IV disease at the time of diagnosis. Both germline BRCA mutation carriers and those with BRCA wild type were included. As part of an exploratory analysis, the patients with BRCA wild type in this study had tumor testing for homologous recombination deficiency to determine its use in predicting outcome. In this trial, the greatest progression-free survival benefit of niraparib was seen in patients with germline BRCA mutations (21 months). Patients with BRCA wild type with tumor homologous recombination deficiency also saw progression-free survival benefit from niraparib (13 months). Less benefit was seen in patients who were biomarker negative–those with BRCA wild type without evidence of tumor homologous recombination deficiency (7 months). Table 1 shows the base case estimates for median progression-free survival by subgroup according to biomarker. Although our base case for our model and model structure primarily uses niraparib data from the NOVA study, similar progression-free survival outcomes have been seen in olaparib as based on the SOLO-2 and Study 19 trials, and rucaparib based on the ARIEL3 trial.7–9
For the observation strategy, progression-free survival was estimated from patients with and without germline BRCA mutations who received placebo in the NOVA trial. Similarly, for the treat-all strategy, progression-free survival was estimated from patients with and without germline BRCA mutations who received niraparib. Among the BRCA wild type cohort, the rate of homologous recombination deficiency positivity was assigned as 54.7%, based on patients without germline BRCA mutations who underwent homologous recombination deficiency tumor analysis. Progression-free quality-adjusted life-years (QALY) were calculated as the product of the progression-free survival for each strategy and its mean estimated utility as determined by the European Quality of Life scale, 5-Dimensions.10 In this scale, an index value of 1 indicates full health. Mean utility was adapted from the supplemental material of the NOVA trial, and was similar between niraparib and placebo arms. In the absence of overall survival data, recent publications in oncology have used cost per progression-free life years gained or progression-free QALYs as measures of cost effectiveness, using a willingness-to-pay cost threshold of an incremental cost-effectiveness ratio greater than $50,000–100,000/progression-free QALY.3,4,11
All patients in the model were assigned to have regular laboratory assessments with a CA 125 drawn every 3 months, regardless of receipt of maintenance therapy strategy. Patients on poly (ADP-ribose) polymerase inhibitor had a weekly complete blood count (CBC) for the first 4 weeks of treatment, followed by a CBC monthly. All patients on maintenance therapy had a monthly visit with their gynecologic oncology provider. If the patient was not on treatment (in the observation cohort), they had an office visit every 3 months. At the time of progression all patients received a computed tomography scan and additional office visit. Patients were assumed to enter the model after receipt of platinum-based chemotherapy for their recurrence, and therefore clinical estimates and costs related to cytotoxic chemotherapy were not included.
Adverse events were modeled to reflect relevant financial consequences of dose reductions and discontinuations based on niraparib use in the NOVA trial. For our base case, all grade 3 and above adverse events were modeled to occur within the first 3 weeks of treatment initiation. Using data from the NOVA trial, 74% of patients on maintenance niraparib would have grade 3 and above adverse events, of which the majority would require a dose reduction from the full dose of 300 mg to 200 mg. We modeled a minority of those patients, approximately 20%, would go on to discontinue treatment. For patients who experienced an adverse event requiring dose reduction, it was assumed that they received 3 weeks of full dose maintenance therapy (300 mg/d), followed by a reduced dose of treatment (200 mg/d) until the time of their estimated disease progression. For patients with an adverse event requiring dose reduction, weekly CBCs were taken for an additional 4 weeks before returning to the regular CBC monitoring schedule. Patients who experienced an adverse event requiring discontinuation received 3 weeks of full dose therapy followed by 1 week of dose reduction (200 mg/d), followed by no further therapy. Patients continued therapy or observation until discontinuation due to adverse event or progression or death.
For our base case, the progression-free survival estimate for patients who had a dose reduction to 200 mg was modeled to be equivalent to those patients who received the full dose of therapy. Given that adverse events were typically observed early in the treatment course, we assumed those patients on therapy who had a discontinuation had a progression-free survival equal to their counterparts who had never taken poly (ADP-ribose) polymerase inhibitor (observation).
Selected costs of clinical care related to each strategy were included (Table 2). Given the short time horizon of less than 24 months, costs were not discounted. For laboratory testing (CA 125, CBC), diagnostic imaging (computed tomography scan of the chest, abdomen, pelvis), office visits, and germline BRCA testing, costs were estimated using Healthcare Common Procedure Coding System or Current Procedural Terminology codes from the clinical diagnostic lab fee schedule and physician fee schedule from the Centers for Medicare & Medicaid Services.12,13 In our base case, half of the patients were assumed to have received germline BRCA testing before entering into the model, and thus 50% of patients in selective strategies were assigned the costs of germline BRCA testing. Cost of homologous recombination deficiency testing was estimated using the out-of-pocket patient charge of $4,040 based on correspondence with Myriad Genetics regarding the used in the NOVA trial. For our base case, cost of niraparib was used, and taken from the wholesale acquisition cost of the medication.14 A 28-day supply at 300 mg/day is $14,769, with a cost per 100 mg capsule of $175.59. No administration costs were included for niraparib beyond office visits with a gynecologic oncologist. Given that the highest proportion of adverse events in the NOVA trial was hematologic, costs of hematologic adverse events was applied, using the lower-end estimate of average per-episode cost adapted from a recent study on chemotherapy-related adverse events in breast cancer, which incorporated both inpatient and outpatient costs.15 Although a minority of patients who experienced adverse events went on to discontinue niraparib in the NOVA trial, to provide a more conservative estimate of adverse event cost, a second cost of adverse events was not applied. All costs were estimated in 2017 U.S. dollars.
Multiple one-way sensitivity analyses were performed to test the clinical and cost assumptions used in the base case model. The rate of germline BRCA mutation carriers in the study population, estimated to be 20% in the base case,16 was varied from 5% to 50%. The cost of adverse events and cost of homologous recombination deficiency testing was varied down to $0. Finally, the cost of poly (ADP-ribose) polymerase inhibitor was tested to determine the cost at which treatment with poly (ADP-ribose) polymerase inhibitor would be cost effective compared with observation given a willingness-to-pay threshold of $100,000/progression-free QALY.
Two alternative scenarios were also modeled to test the key assumptions of the model. In the first scenario, all patients were assumed to have had germline BRCA mutation testing before entering the model. In the second scenario, patients who discontinued niraparib owing to adverse effects were assumed to receive the same full progression-free survival benefit as patients who continued therapy until progression, to test the effect of our base case assumption of equivalence in progression-free survival between patients who discontinued niraparib and observation.
Under our base case assumptions, all maintenance therapy strategies with poly (ADP-ribose) polymerase inhibitor for women with platinum-sensitive recurrent ovarian cancer were both costlier and conferred greater progression-free QALYs than observation (Table 3). Mean costs and progression-free QALY were $827 and 3.4 months for observation, $46,157 and 5.7 for a BRCA-only strategy, $109,368 and 8.5 for a BRCA and homologous recombination deficiency strategy, and $169,127 and 8.8 for a treat-all strategy.
BRCA germline testing followed by selective poly (ADP-ribose) polymerase inhibitor treatment of only those patients with BRCA mutations had an incremental cost-effectiveness ratio of approximately $240,000/progression-free QALY compared with observation. Under a willingness-to-pay cost threshold of $100,000/progression-free QALY, this strategy is not cost effective. The two other maintenance strategies, “treat-all” and “gBRCA and homologous recombination deficiency only” did not approach cost effectiveness. Compared with germline BRCA testing and selective treatment of patients with BRCA mutations, the addition of homologous recombination deficiency screening and treatment of patients with homologous recombination deficiency positive tumors had an incremental cost-effectiveness ratio of $269,883/progression-free QALY. Compared with selective treatment of BRCA mutation carriers and patients with homologous recombination deficiency positive tumors, treatment of all platinum-sensitive recurrent ovarian cancer patients with maintenance poly (ADP-ribose) polymerase inhibitor had an incremental cost-effectiveness ratio exceeding $2 million/progression-free years of life saved.
The estimated additional annual cost to the U.S. health care system of maintenance poly (ADP-ribose) polymerase inhibitor is substantial. Under the least restrictive strategy, treatment of all platinum-sensitive recurrent ovarian cancer patients with maintenance therapy would add an additional $926 million dollars to the health care system compared with observation. Notably, restriction to only germline BRCA patients under the base case 20% rate of germline BRCA mutation carriers in this population would save an additional $677 million compared with a treat-all strategy.
In sensitivity analysis, the prevalence of germline BRCA mutations in the population was varied from 5% to 50%. Across this range, there was no change in cost-effectiveness rankings. In the extreme case of 50% of patients having BRCA mutations, the incremental cost-effectiveness ratio of selective treatment of patients with germline mutations still exceeded $200,000/progression-free QALY compared with observation. As the likelihood of a germline BRCA mutation increases, all poly (ADP-ribose) polymerase inhibitor maintenance strategies become more cost effective compared with observation. Reduction in the cost of adverse events associated with niraparib treatment similarly did not affect cost-effectiveness rankings. In the extreme case where adverse events were assumed to add no additional cost to maintenance niraparib strategies, the incremental cost-effectiveness ratio of selective treatment of patients with germline mutations still exceeded $230,000/progression-free QALY compared with observation. Reduction of the cost of homologous recombination deficiency testing had no effect on cost-effectiveness rankings down to a cost of $0.
The cost of poly (ADP-ribose) polymerase inhibitor was varied over a wide range. Reductions in the 100 mg capsule cost ($175) to the following values would render each strategy potentially cost effective compared with observation with a willingness to pay threshold of $100,000/progression-free QALY: $66 (germline testing); $59 (germline and homologous recombination deficiency testing); $43 (treat- all). Using the current FDA label for maintenance poly (ADP-ribose) polymerase inhibitor for maintenance treatment regardless of biomarker status, the cost per month (28-day supply) would need to be reduced from approximately $14,700 to $3,600 to be considered cost effective compared with observation using a willingness to pay threshold of $100,000/progression-free QALY. Figure 1 illustrates the relative cost effectiveness of each strategy using base case assumptions and at a 60% per-capsule reduction in cost of niraparib. Similar to homologous recombination deficiency testing, reduction in the cost of germline testing had no effect on cost-effectiveness rankings. In the alternative scenario where the cost of germline testing was removed from the model, there was minimal effect on the overall model results. Similarly, cost-effectiveness rankings were unchanged in the alternative scenario where patients who prematurely discontinued niraparib owing to adverse effects were assigned the full progression-free survival benefit as patients who continued therapy until progression. In both cases, the incremental cost-effectiveness ratio of selective treatment of patients with germline BRCA mutations exceeded $200,000/progression-free QALY compared with observation.
This study demonstrates that use of maintenance poly (ADP-ribose) polymerase inhibitor therapy in platinum-sensitive recurrent ovarian cancer is not cost effective compared with observation. Selective maintenance treatment based on either germline BRCA mutation status or homologous recombination deficiency tumor status has a more favorable cost-effectiveness ratio when compared with use in all patients.
To date, published studies of the cost effectiveness of maintenance poly (ADP-ribose) polymerase inhibitor therapy have examined maintenance olaparib. Results were not dissimilar from the current study; however, homologous recombination deficiency status had not previously been included. Smith et al4 used decision-analysis models to compare maintenance olaparib with observation in patients with germline mutations and wild-type BRCA1/2 with platinum-sensitive recurrent ovarian cancer. Maintenance olaparib was not found to be cost effective compared with observation in either population, however, the cost of germline BRCA testing or adverse effects was not included in the Smith et al analysis. Previously, Secord et al3 used decision analysis modeling to compare unselected maintenance olaparib in patients with platinum-sensitive recurrent ovarian cancer and selective maintenance olaparib in patients with germline BRCA1/2 mutations with observation. Similarly, use of maintenance olaparib was found not cost effective regardless of restriction by BRCA1/2 mutation status.
We acknowledge the limitations of this study that may stem from several assumptions made in our model. Although the study used primarily the NOVA trial for base case estimates, our findings of the relative economic effect of use of a targeted therapy in a selected and unselected populations resulting from a broad FDA labeling are applicable across poly (ADP-ribose) polymerase inhibitors. Although we did not seek to directly compare individual poly (ADP-ribose) polymerase inhibitors, the cost profile and outcomes for maintenance olaparib and rucaparib are comparable.17 Additionally, use of the $100,000/progression-free QALY incremental cost-effectiveness ratio threshold may be criticized for lack of applicability in an updated health care landscape.18 The significant burden of the cost of oncologic care may also suggest an exploration of a different willingness-to-pay threshold specific to cancer care.
Other limitations to our cost estimates should be pointed out. To estimate the cost of adverse hematologic effects, we used cost estimates adapted from the breast cancer literature, which may not accurately reflect cost of hematologic adverse events in ovarian cancer patients.15 Interestingly, we found varying the costs of a hematologic adverse event related to niraparib in sensitivity analysis resulted had little effect on the overall results of the model. Finally, our use of the out-of-pocket charge to patients for estimate of the homologous recombination deficiency testing cost may overestimate the true cost estimate of this test, as charges reflect a desired reimbursement rate. Varying the cost of homologous recombination deficiency testing had minimal effect on the model results.
Although poly (ADP-ribose) polymerase inhibitors have recently introduced an alternative to cytotoxic chemotherapy or biologics in both the treatment and maintenance settings for ovarian cancer, the high cost of this therapy is significant. With spending on cancer drugs exceeding $100 billion annually, awareness and considered scrutiny of the value of new therapies is warranted.19 The Society of Gynecologic Oncology has released a position statement on high drug prices and spending and has proposed a number of potential solutions to address this issue.20 In addition to suggesting increased transparency in drug pricing and improving access to generics, the authors highlight the inability of Medicare to negotiate drug pricing, which has resulted in the industry setting cancer drug prices at whatever point the market will bear.21 The subsequent downstream effect is that private insurers largely follow Medicare's lead.
The Society of Gynecologic Oncology’s position statement also recommends the increased study of value-based pricing at the federal level. In the U.S. health care system, there is currently no formal relationship between the efficacy of cancer drugs and drug pricing.22 Solely benchmarking pricing on absolute or relative efficacy of cancer therapy, however, is only one piece of a complex problem. The meaning of value in cancer treatment may differ between patient, physician, and payer, and the magnitude of effect of a therapy on progression-free or overall survival may be weighted differently than the novelty, convenience, effect on quality of life, or adverse effects of a therapy.23 In a recent statement by the American Society of Clinical Oncology on the affordability of cancer drugs,24 the unfortunate conclusion that there is no simple solution to escalating drug prices is unsurprising. Although sobering, this reinforces both the opportunity and need for ongoing research in this area, with the inclusion of a diversity of knowledge and experience of physicians, patients, policymakers, and payers to help inform potential change.
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