The clinical foundation of the analysis is formidable. ENZAMET, led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group and the NHMRC Clinical Trials Centre at the University of Sydney, randomized 1125 men across 83 sites in six countries between March 2014 and March 2017. Half received testosterone suppression plus enzalutamide, a potent androgen receptor pathway inhibitor; the other half received testosterone suppression plus an older non-steroidal antiandrogen such as bicalutamide. Earlier results showed enzalutamide cut the risk of death by roughly 30 percent and the risk of progression by more than half, with benefits maintained out to five years. The new study asked a harder question: what do those gains actually cost?

Unlike most economic evaluations, which lean on mathematical models projecting decades into the future, this analysis used prospectively collected, patient-level data from the trial itself. The researchers tracked hospitalizations, including intensive care and general ward days and emergency department visits, through electronic case report forms. They also linked Medicare and Pharmaceutical Benefits Scheme claims for roughly 45 percent of participants, capturing primary care visits, diagnostic tests, and prescription medicines outside the trial. Quality of life was measured with the EuroQol EQ-5D-5L questionnaire at baseline and then every twelve weeks, generating more than 15,000 individual assessments from 98 percent of participants. The result is an unusually grounded portrait of what treatment actually costs a health system.

The health gains were substantial. Over the first sixty months, men on enzalutamide accrued a mean of 4.25 life-years compared with 3.98 for those on older antiandrogens, and 3.78 progression-free life-years versus 2.66. Adjusted for quality of life, the enzalutamide group gained 0.15 additional quality-adjusted life years, or QALYs, after discounting. Interestingly, while on treatment, the enzalutamide group reported slightly lower utility scores, 0.783 versus 0.810, a difference the authors note did not exceed the minimally important clinical difference of 0.03 for Australian cancer patients, meaning patients on the newer drug did not feel meaningfully worse day to day.

The costs, however, were dominated by the drug itself. At the Australian PBS-listed price of AUD$33 per tablet, taken four tablets daily, enzalutamide accumulated roughly AUD$84.3 million in drug costs across the trial, against under AUD$1 million for the comparator. Per patient, the enzalutamide strategy added AUD$127,262 in discounted costs over five years. Dividing that by the 0.15 QALY gain yields an incremental cost-effectiveness ratio of AUD$835,580 per QALY gained, and AUD$543,880 per life-year saved. Australia’s implicit willingness-to-pay threshold sits near AUD$50,000 per QALY. The drug therefore exceeded the threshold by more than sixteen-fold, a figure consistent with earlier modelled estimates from the United States and China, which reported ratios between roughly US$225,000 and US$509,000 per QALY.

The analysis also uncovered a striking offset that models often miss: once the drug price is excluded, enzalutamide actually saved money. Men on the newer drug spent longer in hospital while on treatment, partly reflecting higher rates of falls and fractures, but they spent far less time in the expensive, progressive, late phase of disease. Total non-drug healthcare costs over five years came to about AUD$60,000 per enzalutamide patient versus AUD$81,300 per comparator patient, a saving of AUD$21,300. In other words, keeping men progression-free longer genuinely reduces downstream spending; the economics fail almost entirely because of the price of the tablets.

Sensitivity analyses made the pricing story vivid. If the per-tablet cost fell to AUD$3, the price of generic versions available in developing countries, enzalutamide became the dominant strategy, costing less and delivering more. At AUD$6.72 per tablet, about 20 percent of the current PBS price, it would meet the AUD$50,000 per QALY threshold. At Denmark’s price of AUD$67 per tablet, the ratio ballooned to nearly AUD$1.85 million per QALY. Probabilistic simulation across 100,000 Monte Carlo replications gave enzalutamide only a 6 percent probability of being cost-effective at the Australian threshold, rising to 16 percent at AUD$100,000. The authors calculate that the price would need to fall by roughly 80 percent for the drug to represent good value at current thresholds.

A further finding deserves attention from clinicians and patients alike. Enzalutamide was associated with higher rates of musculoskeletal complications: falls occurred at 4.1 versus 1.8 per 100 patient-years, and fractures at 2.0 versus 1.1, compared with older antiandrogens. Prescription claims for musculoskeletal and nervous system medications were correspondingly higher in the enzalutamide group. A recent systematic review of eleven randomized trials confirms this signal across the class of potent androgen receptor inhibitors. The authors emphasize that these events are at least partially preventable, and that bone-protective strategies, if properly evaluated and implemented, could improve both the clinical and the economic case for the drug.

The study has limitations the authors acknowledge candidly. Detailed primary care cost data were available only for consenting Australian participants, and trial participants tend to be healthier than the broader population of men with metastatic prostate cancer. The analysis covered only the first five years, during which about 60 percent of enzalutamide patients remained on treatment, and reasons for healthcare use were not captured, making it hard to attribute costs precisely to toxicity. Still, the implications are hard to escape. The clinical benefit of enzalutamide in metastatic hormone-sensitive prostate cancer is real and durable, but at current prices it is priced out of reach of standard cost-effectiveness criteria in Australia and elsewhere. Only five of 23 European health technology assessment agencies offer unrestricted reimbursement in this setting. As patents expire and generics emerge, the arithmetic will change dramatically; until then, the value of this life-extending drug depends less on its biology than on its price.

Subject of Research: Cost-effectiveness of enzalutamide versus standard non-steroidal antiandrogens as first-line therapy for metastatic hormone-sensitive prostate cancer

Article Title: 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)

Article References: Law, C. K., Stockler, M. R., Martin, A. J., Davis, I. D., Sweeney, C. J., & Morton, R. L. (2026). 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). eClinicalMedicine, 100, Article 104207. https://doi.org/10.1016/j.eclinm.2026.104207

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104207

Keywords: enzalutamide, prostate cancer, cost-effectiveness, ENZAMET trial, QALY, androgen receptor inhibitor, metastatic hormone-sensitive prostate cancer, health economics, drug pricing, bone fractures, randomized controlled trial, Pharmaceutical Benefits Scheme