Health technology assessment of four drugs for patients with metastatic castration resistant prostate cancer

Prostate cancer is the most common cancer among Norwegian men and represents nearly 20 % of all new cancer cases. Most prostate cancers develop slowly, but metastatic prostate cancer is not currently curable. Several new drugs for treatment of metastatic prostate cancer have been developed during the last years. It is, however, unclear which of these new drugs are most effective and cost-effective. This health technology assessment aims at examining the relative effectiveness and cost–effectiveness of four drugs (abiraterone, cabazitaxel, enzalutamide and radium-223) for metastatic castration resistant prostate cancer.

To assess the clinical effectiveness, safety and cost-effectiveness of the new drugs used for patients with metastatic castration resistant prostate cancer relative to each other.

We have performed this Health Technology Assessment in accordance with our Handbook.

We performed a systematic literature search for randomized controlled trials in October 2015 in relevant bibliographic databases. We contacted relevant pharmaceutical companies to obtain additional information. Full text publications of potentially eligible references were retrieved. Two authors reviewed eligible publications independently to identify publications that fulfilled our pre-specified inclusion criteria. We assessed all included studies for risk of bias. One author extracted data from the included clinical trials using a pre-designed data recording form and another author verified the data.

We conducted pairwise meta-analyses for each available endpoint for all possible combinations of interventions and controls with available evidence from included trials. We performed network-meta-analyses where appropriate according to population, intervention, control and outcome. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint by help of the surface under the cumulative ranking curve (SUCRA).

Two authors assessed the quality of the direct evidence, indirect evidence and the combined evidence from the network meta-analyses by using the GRADE methodology.

Our cost-effectiveness analysis was based on a probabilistic, discrete-time Markov cohort model with three health states: progression free survival, progressed disease and death. We ran separate models for the post-docetaxel and docetaxel-naive patient groups. The post-docetaxel model included all four medications, while the docetaxel-naive model examined only abiraterone and enzalutamide. We adjusted baseline transition probabilities using hazard ratios from the effect section of this report. Clinical experts provided advice about resource use during the course of treatment that we used in cost estimations for the model.

We relied on maximum pharmacy retail prices in the cost-effectiveness analyses because price discounts negotiated by the Drug Procurement Cooperation and the pharmaceutical companies are considered confidential.

Our results for clinical effectiveness are based on eight randomized controlled trials, presented in 16 publications. The trials included a total of 7,314 patients, from more than 20 countries in Europe, North America and Asia, with histologically or cytologically confirmed diagnosis of progressive prostate cancer with soft tissue or bone metastases.

Our clinical evaluation based on the direct comparisons shows that for the all patients group (patients that had, or had not received chemotherapy), the four drugs probably increase median overall survival slightly compared with passive treatment. Median overall survival was increased by approximately four months for all treatment groups (HR 0.77 (95 % CI 0.70 to 0.93) for abiraterone, HR 0.70 (95 % CI 0.59 to 0.83) for cabazitaxel, HR 0.68 (0.59 to 0.79) for enzalutamide and HR 0.65 (95 % CI (0.48 to 0.87) for radium-223. We have low to moderate confidence in these estimates. All intervention drugs probably increases the progression free survival period slightly (between one to five months) compared with passive treatment (moderate quality evidence). Hazard ratio was 0.56 (95 % CI 0.44 to 0.70) for abiraterone, 0.75 (95 % CI 0.63 to 0.90) for cabazitaxel, 0.22 (95 % CI 0.16 to 0.30) for enzalutamide and 0.64 (0.54 to 0.77) for radium-223). The drugs probably improves the quality of life slightly (moderate quality evidence), but may cause more serious adverse events (abiraterone, cabazitaxel, radium-223) or there may be little or no difference between the treatment groups (enzalutamide) (low or moderate quality evidence). The follow up time in the studies varied from 12 to 49 months.

In the docetaxel-naive model incremental cost-effectiveness ratios, which reflect the minimum willingness-to-pay at which a treatment could potentially be considered cost-effective, were NOK 984,163 for abiraterone and NOK 971,465 for enzalutamide.

In the post-docetaxel model the incremental cost-effectiveness ratios were NOK 993,004 for radium-223; NOK 789,128 for abiraterone; NOK 1,210,474 for cabazitaxel; and NOK 809,595 for enzalutamide.

At a willingness-to-pay of NOK 500,000, to be considered cost-effective for use among docetaxel-naive patients, the prices of abiraterone and enzalutamide would need to drop by approximately 54% and 55%, respectively. For use among post-docetaxel patients treatments could be considered cost-effective with price declines of 47% for abiraterone, 46% for enzalutamide, 67% for radium-223 and 37% for cabazitaxel.

Scarcity of data is a limitation of this report. Only one or two head-to-head trials have been performed for each comparison versus placebo or “passive” treatment. We did not find any trials that have tested our interventions against each other directly. We therefore mainly present estimates of effect for head-to-head comparisons between the intervention and placebo or “passive” treatment. Our estimates for the comparisons between the interventions are therefore only based on indirect estimates and must be interpreted cautiously.

Our economic analysis has a number of limitations that should be considered when interpreting the cost-effectiveness results. One important caveat is that the analysis only examines the cost-effectiveness of included treatments, and does not address the best sequencing of these medications in prostate cancer treatment.

Because baseline survival information for the control arms was extrapolated beyond the end of trial follow-up periods, there is likely to be a good deal of uncertainty in our estimates of overall and progression-free survival in the model.

There is a large degree of uncertainty around the utility values used to capture health-related quality of life. Although, in the base case scenario, we applied the same utility values for all active treatments among patients with the same docetaxel status, the utility values reported in the literature varied widely among treatments.

We have assessed the clinical effectiveness, safety and cost-effectiveness of abiraterone, cabazitaxel, enzalutamide and radium-223 for patients with metastatic castration resistant prostate cancer relative to each other.

Our cost-effectiveness analysis indicates that at today’s maximum pharmacy prices (AUP) none of the medications investigated can be considered cost-effective at what has typically been considered a reasonable willingness-to-pay.

For the docetaxel-naive patient group rebates on the AUP prices of approximately 54% for abiraterone and 55% for enzalutamide would be necessary for these medications to be cost-effective at a willingness-to-pay of NOK 500,000 per quality-adjusted life year. For post-docetaxel patients, the required rebates would be 47% for abiraterone, 46% for enzlutamide, 67% for radium-223 and 36% for cabazitaxel.