Progression from clinically localized, hormone-naïve prostate cancer to metastatic castration-resistant prostate cancer (CRPC) is ultimately fatal, with currently no available curative treatments.1,2 The standard of care for patients with metastatic CRPC was chemotherapy and palliative hormone suppression until the 2011 approval of abiraterone, a potent androgen biosynthesis inhibitor.1,2 Abiraterone has been shown to extend the time to disease progression and overall survival in chemotherapy-naïve patients with refractory, metastatic disease, making it a powerful tool for the treatment of patients with metastatic CRPC.3,4
Using mathematical modeling and evolutionary dynamics, Zhang and colleagues hypothesized that continuous abiraterone treatment leads to “competitive release” of abiraterone-resistant tumor cells (ie, rapid proliferation of abiraterone-resistant tumor cell populations once abiraterone-sensitive cells that compete for resources are eliminated by treatment). By retaining a significant population of treatment-sensitive tumor cells to act as competitors, the growth of treatment-resistant cell populations will be slowed, extending the time to disease progression.
Zhang and colleagues developed an adaptive abiraterone therapy approach based on patient-specific prostate-specific antigen (PSA) levels as a biomarker to establish the on- or off-treatment cycles of abiraterone therapy, with a goal of maintaining a competing population of abiraterone-sensitive tumor cells rather than eliminating the majority of abiraterone-sensitive cells, as is the case with continuous dosing of abiraterone plus prednisone. The results of a small clinical trial demonstrated that adaptive abiraterone dosing could prolong the time to disease progression and reduce the cumulative dose of chemotherapy that patients receive.5
Updated results from the clinical study by Zhang and colleagues at Moffitt Cancer Center demonstrated a doubling of the time to disease progression in patients who received treatment using the adaptive abiraterone plus prednisone therapy strategy compared with a contemporaneous cohort of patients who received standard of care with continuous abiraterone therapy plus prednisone.6,7
Based on the encouraging clinical results of the study, we performed an economic analysis to determine the financial impact of administering adaptive abiraterone therapy compared with continuous therapy.5,7 We hypothesized that the cost of care would be reduced in patients receiving adaptive abiraterone therapy, because they would receive less cumulative drug doses, and they may have less severe or less frequent adverse events. Our study compares the cost of care for patients who received adaptive abiraterone therapy versus patients who received continuous abiraterone therapy.
All patients with metastatic CRPC who had Eastern Cooperative Oncology Group status of 0 or 1 and no visceral metastasis between June 1, 2012, and December 31, 2017, at H. Lee Moffitt Cancer Center, a large National Cancer Institute–designated cancer center in Tampa, FL, were eligible to participate in an interventional trial, on which our analysis is based.5 Patients who had at least 6 months of follow-up after receiving the first dose of abiraterone were included in our cost analysis.
The patients in the adaptive abiraterone therapy cohort (N = 15) received 1000 mg of abiraterone plus prednisone daily until a target PSA level of 50% reduction from their pre–abiraterone treatment PSA was reached (ie, the target threshold). Treatment with abiraterone and prednisone was discontinued until their PSA levels rose above the target threshold, which triggered the reintroduction of abiraterone plus prednisone until the PSA levels fell below the threshold. These therapy cycles continued until radiographic progression.
The clinical characteristics were the same for the 21 patients in the continuous therapy cohort, who received 1000 mg of abiraterone plus prednisone daily, until radiographic progression.
We reviewed the charts of 36 patients who began either adaptive or continuous abiraterone therapy between June 1, 2012, and December 31, 2017, to determine time to radiographic progression. The costs of care were calculated for all patients, beginning with the first dose of abiraterone until treatment was stopped because of radiographic progression.
Our study was done from the perspective of the Centers for Medicare & Medicaid Services (CMS) as a third-party payer, and thus the costs are reported using CMS reimbursement rates for individual Current Procedural Terminology ( CPT) procedure codes that were calculated using Moffitt Cancer Center’s billing records. The cost of each CPT was standardized to the CMS 2018 fee schedules. All reimbursement rates were inflation adjusted to 2018 US dollars. No discount rate was applied, because no future projections were created.
The mean total annual cost of care per patient was calculated by averaging the annualized cost of care for each individual patient. The annualized cost of care for each patient was calculated by dividing the total cost of care over the course of the study by the time to disease progression in years. The costs were separated into the cost of abiraterone and the cost of ancillary care, which were reported by clinical category (eg, chemotherapy, nonchemotherapy pharmacy, laboratory, radiology, and inpatient stay).
The duration of abiraterone treatment was calculated through chart review to determine the days patients received therapy, based on the date of the initial treatment and the date of termination, as well as breaks in therapy.
The cost of abiraterone was determined using the average wholesale price of $108 per 250-mg dose,8 with a 13% discount, as recommended by the Academy of Managed Care Pharmacy guidelines.8,9 The cost and resource utilization for ancillary services were calculated using line item billing data for each patient, with reimbursement based on Medicare contracted rates.Statistical Analysis
Descriptive statistics and 2 sample t-tests were performed using Stata 15 (StataCorp LLC; College Station, TX). Besides presenting information on the potential significant differences between the 2 treatment groups, we also wanted to assess the practical significance and size of the difference in cost between these treatment groups.
Effect sizes were calculated using Cohen’s d and Hedge’s g measures, which express the difference in the outcome measures in units of the standard deviations of the outcome variable.
The mean total annual cost of care per patient for the cohort of patients (N = 15) who received adaptive abiraterone therapy was $79,093 compared with a mean total annual cost of care of $146,782 per patient for the patients (N = 21) who received continuous abiraterone therapy (P <.0001; Figure).
In assessing the effect size of the treatment group on the total costs, our Cohen’s d estimate was –2.14, which indicates that the total annual cost of care per patient for the adaptive therapy group was almost 3 standard deviations lower than the total annual cost of care per patient for the continuous therapy group. In addition, the 2 sample t-tests demonstrated a significant difference (P <.0001), despite the small sample size.
The majority of the cost-savings in the adaptive therapy group was a result of the reduced use of abiraterone. The patients in the adaptive therapy group received 50% less abiraterone therapy than the patients in the continuous therapy group. This reduction in drug use yielded more than double the median time to disease progression for the adaptive therapy cohort than in the continuous therapy cohort, 25.8 months versus 12.1 months, respectively (Table; P =.0031). At the end of the study period, 6 of the 15 patients in the adaptive therapy group remained in the study, with no radiographic progression, compared with only 3 of the 21 patients in the continuous therapy group who remained in the study.
The mean annual ancillary cost of care was calculated to determine if the cost of care differs between the adaptive and continuous therapy cohorts when excluding abiraterone from the analysis, because of its high cost and substantial reduction in use, as demonstrated above. The average annual ancillary care cost of adaptive therapy per patient was $13,883, excluding treatment with abiraterone. By comparison, the continuous therapy group had an average total annual ancillary cost of care per patient of $22,322, excluding treatment with abiraterone (Table; Figure). Although the results differ by nearly $10,000, the results were not statistically significant (P = .2757), and the effect size (ie, Cohen’s d of –0.37) is not large because of the large difference in ancillary cost per patient for the continuous therapy cohort.
Although the overall annual cost of ancillary care per patient was not significant, nonchemotherapy pharmacy costs, which include all drugs administered, excluding abiraterone, were significantly higher for the continuous therapy cohort than for the adaptive therapy cohort, $7745 and $1392, respectively (Table; P = .0240). Of the $7745 per-patient nonchemotherapy pharmacy costs, $4848 was attributed to denosumab administration, a drug used to prevent bone loss in patients receiving abiraterone. By contrast, the radiology costs per patient were higher for the adaptive therapy group than for the continuous therapy group, $6593 versus $2672, respectively (Table; P = .0001).
Based on the results of the previously mentioned study, the clinical results of an adaptive abiraterone therapy suggest that patients with CRPC can significantly extend the time to disease progression and reduce drug use by 47% when this strategy is personalized using the patient’s PSA level rather than continuous abiraterone therapy.5 Our study builds on those clinical results, demonstrating that adaptive abiraterone therapy reduces the annual cost of care per patient by $67,689 (ie, $146,782 –$79,093) compared with continuous therapy, while extending the time to disease progression.
This annual per-patient cost-savings is driven by the reduction in abiraterone use. Generic versions of abiraterone were approved in 2018 and 2019, which could have reduced the cost of the drug and, therefore, decreased the savings provided by the adaptive therapy approach. The brand-name version of abiraterone is listed at an average wholesale price of $108 per 250-mg dose, whereas the generic versions are listed between $14 and $97 per 250-mg dose.9
The majority of generic abiraterone manufacturers list the cost per dose at either $92 or $97 per 250-mg dose, resulting in a 17% cost reduction compared with the brand-name drug.9 Therefore, the assumption is that a significant savings per patient would still be observed by using the adaptive therapy approach. Regardless, even when comparing the least expensive generic drug, adaptive abiraterone therapy will reduce costs, albeit by a much smaller amount, and extend the time to disease progression.
Although the overall cost of all care, excluding treatment with abiraterone, was not statistically significant, patients receiving continuous therapy had a statistically significant increase in nonchemotherapy pharmacy costs of $7745 compared with $1392 for adaptive therapy. These costs include all supportive care drugs administered and excluded abiraterone. Most of this cost difference, namely, $4848 of the $7745, respectively, resulted from the increased use of denosumab to mitigate bone loss in patients receiving continuous therapy, because abiraterone therapy disrupts hormone synthesis leading to reduced bone density. Of note, the radiology costs were significantly higher in patients receiving adaptive therapy compared with continuous therapy ($6593 vs $2672, respectively) because of increased monitoring and staging scans, as part of the clinical trial. The emerging evidence on the efficacy of adaptive abiraterone therapy suggests that there may be additional opportunities to reduce and optimize radiologic scans that would further enhance the value of adaptive abiraterone therapy.5,7
The cost-savings of using the adaptive abiraterone therapy strategy in this study demonstrates the value that personalized medicine can generate. CMS would be expected to save $67,689 per patient with metastatic CRPC annually when the patients receive adaptive abiraterone therapy versus continuous therapy.
In addition, adaptive therapy doubled the time to disease progression in our study, which translates into an additional year of effective treatment for only $11,404 ($158,186 for 2 years of adaptive therapy vs $146,182 for 1 year of continuous therapy).
Delaying the need for additional lines of therapy, which tends to be more costly and less effective, is another benefit to this approach. The large financial impact of delaying therapy extends to patients, who are often responsible for high copays for anticancer drugs, such as abiraterone, as well as deductibles plus coinsurance for ancillary care and services.9-11
A study by Knight and colleagues reports that a lower financial burden improves outcomes and compliance, and reduces the discontinuation of therapy as a result of cost.12 Ratain and colleagues discussed several clinical studies of innovative approaches that can enhance the value of cancer care and offer important clinical, financial, and societal benefits.13
Based on our study, the cost-savings and clinical benefits, if observed in a larger study, would provide a strong rationale for adopting adaptive abiraterone therapy as standard practice to yield a longer time to progression of disease, at a much lower cost. Therefore, a larger, multisite trial is warranted to further strengthen the evidence for adaptive abiraterone therapy. A significantly larger number of patients will be required to ensure appropriate statistical power to make conclusions regarding clinical and financial outcomes. Furthermore, extending the follow-up time will allow for more concrete clinical outcomes, such as overall survival and progression-free survival.
A recent commentary by Ratain and colleagues has described other innovative, successful approaches to dosing adaptive therapy of multiple anticancer therapies.13 One example using abiraterone is the randomized clinical trial comparing standard fasting-dose adaptive abiraterone therapy with reduced-dose adaptive abiraterone therapy with a meal, which provides robust support for the practical use of adaptive abiraterone therapy14 and has now been incorporated into the National Comprehensive Cancer Network guidelines.15 There is an opportunity for scientific, clinical, and financial innovation to drive new ways of administering chemotherapy, which will improve disease control at a sustainable cost.
The primary limitation of this study is its small sample size. This preliminary study was conducted to investigate the potential benefits of using an adaptive, personalized approach to abiraterone therapy for metastatic CRPC, and to build the case for a larger, more robust clinical study in a bigger cohort. Although the sample size is small, the effect size is significant, and the mean annual cost of care for adaptive abiraterone therapy is significantly lower than for continuous therapy. This suggests that a larger study is warranted to validate these findings.
Another limitation is the possibility that patients received treatment-related care outside of Moffitt Cancer Center (eg, emergency department, urgent care), but there is no evidence to suggest that one cohort would use these services more than the other, and the Moffitt Cancer Center has an emergency department–like Direct Referral Center available, where patients can receive emergency care.
A 2016 review of the state of precision medicine in Nature Reviews Genetics outlined several successful precision medicine strategies that are now standard of care.16 The oncology examples provided are well-known treatments targeting specific genetic variants found in tumor cells, such as gefitinib for EGFR and crizotinib for ALK genomic mutations in lung cancer.17,18 However, precision medicine does not require sophisticated tumor testing for genetic markers in all cases.
Practical precision medicine strategies, such as this adaptive abiraterone approach or pharmacogenomics-targeted dosing, can use known biomarkers to tailor therapy, generate improved outcomes, and reduce costs without the need for novel drug and diagnostic discovery and development. Furthermore, the study’s findings suggest that a larger clinical study of adaptive abiraterone therapy is warranted to validate the potential to extend the time to disease progression and reduce the costs of treatment of metastatic CRPC.
Author Disclosure Statement
Mr Mason owns stock of and is a board member of Interpares Biomedicine; Dr Pow-Sang has no conflicts of interest to report; Dr Peabody is owner and president of QURE; Dr Letson is a consultant to Stryker Ortho; Dr Zhang is a consultant to Dendreon, is on the Speaker Bureau of Merck and Sanofi, and has received advisory board honoraria from AstraZeneca, Bayer, Clovis Oncology, Janssen, and Seagen, Inc; Dr McLeod is a Board of Directors member and has stock options of Cancer Genetics, co-founder and owns stocks of Interpares Biomedicine, co-founder and owns stocks of Clariifi, Medical Advisory Committee member of and receives honoraria from eviCORE Healthcare, serves on the Speakers Bureau for Genentech and receives honoraria from Genentech, and Medical Advisor and owns stocks of Pharmazam; Mr Burkett, Dr Nelson, Dr Gatenby, and Dr Kubal have no conflicts of interest to report.
This work was supported by grants from the DeBartolo Family Personalized Medicine Institute and the National Institutes of Health (U01 HG007437, R01 CA161608, R01 CA170595, P30 CA07629, and U54 CA143970-05). The funders had no role in the design and conduct of the study.
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- Nuhn P, De Bono JS, Fizazi K, et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. Eur Urol. 2019;75:88-99.
- Ryan CJ, Smith MR, de Bono JS, et al; for the COU-AA-302 investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148. Erratum in: N Engl J Med. 2013;368:584.
- de Bono JS, Logothetis CJ, Molina A, et al; for the COU-AA-301 investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
- Zhang J, Cunningham JJ, Brown JS, Gatenby RA. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat Commun. 2017;8:1816.
- Hahn AW, Higano CS, Taplin ME, et al. Metastatic castration-sensitive prostate cancer: optimizing patient selection and treatment. Am Soc Clin Oncol Educ Book. 2018;38:363-371.
- Zhang J, Fishman MN, Brown J, Gatenby RA. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer (mCRPC): updated analysis of the adaptive abiraterone (abi) study (NCT02415621). J Clin Oncol. 2019;37(15_suppl):Abstract 5041.
- Micromedex RED BOOK. www.ibm.com/products/micromedex-red-book. Accessed November 20, 2020. [Requires subscription.]
- Academy of Managed Care Pharmacy. AMCP Guide to Pharmaceutical Payment Methods, 2013 Update. Version 3.0. Alexandria, VA; 2013. www.amcp.org/sites/default/files/2019-03/Full-Pharmaceutical-Guide-%283.0%29.pdf. Accessed November 19, 2020.
- Dusetzina SB, Bach PB. Prescription drugs—list price, net price, and the rebate caught in the middle. JAMA. 2019;321:1563-1564.
- Dusetzina SB, Conti RM, Yu NL, Bach PB. Association of prescription drug price rebates in Medicare Part D with patient out-of-pocket and federal spending. JAMA Intern Med. 2017;177:1185-1188.
- Knight TG, Deal AM, Dusetzina SB, et al. Financial toxicity in adults with cancer: adverse outcomes and noncompliance. J Oncol Pract. 2018;14:e665-e673.
- Ratain MJ, Goldstein DA, Lichter AS. Interventional pharmacoeconomics—a new discipline for a cost-constrained environment. JAMA Oncol. 2019;5:1097-1098.
- Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018;36:1389-1395.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate Cancer. Version 3.2020. November 17, 2020. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed November 20, 2020.
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- Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8:823-859. Erratum in: J Thorac Oncol. 2013;8:1343.
- Blumenthal GM, Mansfield E, Pazdur R. Next-generation sequencing in oncology in the era of precision medicine. JAMA Oncol. 2016;2:13-14.