Enzalutamide has demonstrated significant survival benefits in patients with metastatic hormone-sensitive prostate cancer (mHSPC), but its high treatment cost has raised questions about the economic value of prolonged therapy. Although previous economic evaluations have relied largely on modeled outcomes, the phase 3 ENZAMET trial provides an opportunity to assess cost-effectiveness using prospectively collected clinical and healthcare utilization data.
In October 2026, eClinicalMedicine published a prespecified secondary endpoint analysis of ENZAMET titled “Cost-effectiveness of adding enzalutamide vs standard non-steroidal antiandrogen drugs for patients with metastatic hormone-sensitive prostate cancer undergoing standard first-line therapy: a within-trial, secondary end-point analysis of the ENZAMET phase 3, international randomized trial (ANZUP 1304).”
The analysis evaluated the cost-effectiveness of adding enzalutamide to testosterone suppression compared with conventional non-steroidal antiandrogen therapy during the first 5 years after randomization, from an Australian health system perspective.
Authors: Chi Kin Law, Martin R. Stockler, Andrew J. Martin, Ian D. Davis, Christopher J. Sweeney, and Rachael L. Morton.
ENZAMET Trial Design and Economic Evaluation
ENZAMET (ANZUP 1304; NCT02446405) was an international, open-label, randomized phase 3 trial involving 1,125 patients with mHSPC from 83 centers across six countries.
Patients were randomized 1:1 to receive testosterone suppression plus either enzalutamide 160 mg daily (n = 563) or a conventional non-steroidal antiandrogen, such as bicalutamide (n = 562). Early docetaxel was permitted at clinician discretion. Previous ENZAMET analyses demonstrated significant improvements in overall survival (HR 0.70; 95% CI 0.58–0.84) and progression-free survival (HR 0.45; 95% CI 0.39–0.53) with enzalutamide compared with conventional antiandrogen therapy.
The current economic analysis used data collected through January 19, 2022, with a median follow-up of 68 months. Investigators assessed healthcare utilization, hospitalization, prescription medication costs, and health-related quality of life during the first 60 months after randomization.
Quality-adjusted life years (QALYs) were estimated using EQ-5D-5L health utility scores collected during study treatment, with an externally derived utility value applied after treatment discontinuation or progression. Costs were expressed in 2023 Australian dollars. Costs and health outcomes occurring more than 12 months after randomization were discounted at 5% annually.
Survival and Quality-Adjusted Outcomes at 5 Years
During the first 60 months after randomization, patients receiving enzalutamide accumulated a mean of 4.25 life-years compared with 3.98 life-years among those receiving conventional non-steroidal antiandrogen therapy.
The difference was greater for progression-free survival, with 3.78 progression-free life-years in the enzalutamide group versus 2.66 years in the comparator group. After discounting, the enzalutamide group accumulated 3.90 life-years compared with 3.66 life-years in the conventional therapy group, representing an incremental gain of 0.24 life-years.
Quality-adjusted survival also favored enzalutamide:
- Discounted QALYs: 3.02 versus 2.87, corresponding to an incremental gain of 0.15 QALYs.
- Undiscounted QALYs: 3.29 versus 3.11.
- Quality-adjusted progression-free life-years: 2.95 versus 2.17 before discounting.
Among participants assessed while receiving study treatment, mean EQ-5D-5L utility scores were slightly lower with enzalutamide than with conventional antiandrogen therapy (0.783 versus 0.810; p < 0.0001). However, the difference did not exceed the commonly used minimally important clinical difference of 0.03 cited by the investigators.
Cost-Effectiveness of Enzalutamide
Despite improved survival outcomes, the additional cost of enzalutamide resulted in an incremental cost-effectiveness ratio substantially exceeding the willingness-to-pay threshold used in the analysis. At the Australian Pharmaceutical Benefits Scheme-listed price of approximately AUD$33 per 40-mg tablet, the enzalutamide group incurred an additional AUD$127,262 in discounted total healthcare costs, including study treatment, per patient compared with conventional non-steroidal antiandrogen therapy. The incremental cost-effectiveness ratios were:
- AUD$543,880 per life-year gained
- AUD$835,580 per QALY gained
The estimated cost per QALY was substantially higher than the AUD$50,000 willingness-to-pay threshold used in the analysis. Drug acquisition costs were the principal driver of the difference, contributing an additional AUD$148,607 per patient after discounting.
However, when study drug costs were excluded, patients receiving enzalutamide incurred lower overall healthcare expenditure than those receiving conventional antiandrogen therapy. Discounted non-study-drug healthcare costs averaged approximately AUD$60,000 per patient in the enzalutamide group compared with AUD$81,300 in the comparator group.
Although non-study-drug healthcare costs were higher during study treatment with enzalutamide, recorded off-treatment Medicare costs were substantially lower than in the comparator group. The investigators attributed this difference in part to the shorter duration of progressive disease in the enzalutamide group.
How Would Lower Drug Prices Affect Cost-Effectiveness?
Sensitivity analyses identified the price of enzalutamide as the main factor influencing cost-effectiveness estimates. At approximately AUD$6.72 per 40-mg tablet, representing a reduction of nearly 80% from the PBS-listed price used in the analysis, the estimated incremental cost-effectiveness ratio reached AUD$50,000 per QALY gained.
In a sensitivity analysis assuming an enzalutamide price of AUD$3 per tablet, enzalutamide became a dominant strategy, providing greater estimated health benefits at lower overall costs than conventional non-steroidal antiandrogen therapy. Variations in other cost inputs and health utility assumptions did not change the overall conclusion that enzalutamide was unlikely to be cost-effective at the PBS-listed price used in the analysis.
In probabilistic sensitivity analyses involving 100,000 simulations, enzalutamide had a 6% probability of being cost-effective at a willingness-to-pay threshold of AUD$50,000 per QALY gained. This probability increased to 16% when the threshold was raised to AUD$100,000 per QALY.
Healthcare Utilization and Bone Health
Patients assigned to enzalutamide accumulated approximately 47% more person-days on study treatment than those receiving conventional antiandrogen therapy, consistent with longer treatment exposure. During treatment, enzalutamide was associated with slightly greater intensive care and general hospital ward utilization after adjustment for treatment exposure. No significant differences were observed in high-dependency unit stays or emergency department presentations.
The investigators also identified a higher proportion of prescription claims for musculoskeletal medications among patients receiving enzalutamide. These findings were considered alongside previously reported ENZAMET safety data showing higher rates of all-grade falls (4.1 versus 1.8 per 100 patient-years) and fractures (2.0 versus 1.1 per 100 patient-years) with enzalutamide compared with conventional antiandrogen therapy.
Although the economic analysis could not directly attribute individual healthcare costs to specific adverse events, the investigators emphasized the importance of long-term bone health management in patients receiving potent androgen receptor pathway inhibitors.
Interpreting the ENZAMET Economic Findings
Using prospectively collected ENZAMET data, the investigators found that adding enzalutamide improved quality-adjusted survival but resulted in an incremental cost-effectiveness ratio above the willingness-to-pay threshold used in the Australian analysis.
Several limitations should be considered when interpreting these findings. Although ENZAMET enrolled patients internationally, linked primary-care and prescription claims data were available only for consenting Australian participants, limiting the generalizability of cost estimates to other healthcare systems. The analysis was also restricted to the first 5 years after randomization, although approximately 60% of participants assigned to enzalutamide remained on treatment beyond that period.
Furthermore, hospitalizations and other healthcare costs after disease progression, including subsequent treatment and palliative care, were not comprehensively captured. The reasons for individual healthcare encounters were also unavailable, preventing the investigators from attributing specific costs to treatment-related adverse events. These limitations introduce uncertainty into the estimates of longer-term healthcare costs. The findings therefore reflect cost-effectiveness within the Australian healthcare system and at the drug prices used in the analysis, rather than establishing the economic value of enzalutamide across different healthcare systems.
Conclusion
Building on the previously demonstrated survival benefit of enzalutamide in mHSPC, the prespecified ENZAMET economic analysis found improved quality-adjusted survival but indicated that enzalutamide was unlikely to be cost-effective at the Australian PBS-listed price used in the study. The estimated incremental cost-effectiveness ratio of AUD$835,580 per QALY gained substantially exceeded the study’s willingness-to-pay threshold, with drug acquisition costs accounting for most of the additional expenditure.
Drug pricing was the main driver of the cost-effectiveness findings, while longer treatment duration and potential treatment-related complications, including falls and fractures, were additional considerations in assessing the healthcare costs associated with enzalutamide.
The full article is available in eClinicalMedicine.
