2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

The Hospitalization-Related Costs of Adverse Events for Novel Androgen Receptor Inhibitors in Non-Metastatic Castration-Resistant Prostate Cancer: An Indirect Comparison - Beyond the Abstract

The FDA’s approval of the second-generation androgen receptor inhibitors (SGARIs)—apalutamide, enzalutamide, and darolutamide—in 2018‒2019 expanded therapeutic options for patients with non-metastatic castration resistance prostate cancer (nmCRPC) but has also raised the critical question of patient treatment selection. Although no head-to-head trials have directly compared the three SGARIs, the phase III, placebo-controlled trials of enzalutamide (PROSPER),1 apalutamide (SPARTAN),2 and darolutamide (ARAMIS)3 demonstrated that all three treatments significantly prolonged metastasis-free survival (all p < 0.001) and improved overall survival.4,5 Evidence from indirect comparisons using network meta-analysis (NMA) and matching adjusted indirect comparison (MAIC) techniques found that all the SGARIs demonstrated consistent benefits in both metastatic-free survival and overall survival (OS).6-10 Wenzel et al concluded that: “Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order.”10 With regard to safety and tolerability, significant differences in their respective profiles were demonstrated in indirect treatment comparisons. For instance, using a MAIC approach, Halabi et al. found that darolutamide offered a more favorable tolerability profile after adjusting for cross-trial differences.8

In this manuscript, we estimate the economic impact of specific safety differences between the ARIs by comparing their hospitalization costs from adverse events (AEs) of special interest in nmCRPC. In particular, we evaluated differences in mean per-patient costs of all-cause AEs requiring hospitalization between darolutamide versus apalutamide and enzalutamide after adjusting for patient baseline differences, via a MAIC. We find that after weighting, estimated mean costs for grade ≥ 3 AEs, assumed to require hospitalization, were lower for patients with nmCRPC treated with darolutamide than for patients treated with apalutamide (by $1021) or enzalutamide (by $415). The largest drivers of these higher costs compared with darolutamide were fractures, hypertension and rash, for apalutamide, and fatigue (not including asthenia) and hypertension, for enzalutamide. It should be noted that these results focus on AE-related immediate hospitalization costs and do not include costs from other care settings (outpatient, rehab, home health, etc.), drug-drug interactions (DDIs), or cascading events. Importantly, the analysis ignored any differences in grade 1–2 events, which may further extend the direct medical cost differences. Lastly, indirect costs, such as productivity losses, impact on caregivers, etc., which can also contribute to the full cost burden from the treatments’ safety differences, were not included.

In a forthcoming commentary, we take an expanded look at the three SGARIs’ safety profiles and discuss potential implications for treatment selection. In particular, we examine the differing potential for DDIs and various types of AEs across the three treatments and discuss considerations in light of the nmCRPC population and recent evidence from patient preference studies. We also examine the issue of cascading events following treatment-emergent AEs. Many AEs do not occur as isolated events but instead act as tipping points that trigger a cascade of healthcare interventions. For example, dizziness may lead to falls, which in turn may lead to fractures—events that can be particularly concerning in an older patient population, precipitating major disability and even loss of independence. These situations can be further complicated by “prescribing cascades,” scenarios in which the AE event is misinterpreted as a new medical condition, and a new drug is prescribed to treat this drug-induced AE without recognizing the original driver. Finally, AEs can contribute to cascade events through treatment disruptions to the patient’s SGARI. For instance, AEs can prompt dose interruptions or reductions, or diminished treatment adherence, resulting in decreased efficacy of the patient’s cancer treatment, necessitating additional rounds of intervention and care activities. These cascading events not only add to healthcare costs, but can increase the physical, emotional, and quality-of-daily-life harms experienced by patients and their caregivers. Jointly, these two papers describe safety and tolerability profile considerations that prescribers should weigh carefully when choosing SGARIs for patients with nmCRPC.  

Written by: Neal Shore, Shan Jiang, Viviana Garcia-Horton, Emi Terasawa, David Steffen, Andi Chin, Rajeev Ayyagari, Jamie Partridge, A Reginald Waldeck

Carolina Urologic Research Center, Myrtle Beach, SC, USA; Bayer, Whippany, Whippany, NJ, USA; Analysis Group, Inc., New York, NY, USA; Analysis Group, Inc., Boston, MA, USA.

References:

  1. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018/06/28 2018;378(26):2465-2474. doi:10.1056/NEJMoa1800536
  2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018/04/12 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
  3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019/03/28 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671
  4. Saad F, Bögemann M, Suzuki K, Shore N. Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors. Prostate Cancer and Prostatic Diseases. 2021;24(2):323-334.
  5. Wang L, Paller C, Hong H, et al. Comparison of treatments for nonmetastatic castration-resistant prostate cancer: matching-adjusted indirect comparison and network meta-analysis. JNCI: Journal of the National Cancer Institute. 2022;114(2):191-202.
  6. Maggi M, Salciccia S, Del Giudice F, et al. A systematic review and meta-analysis of randomized controlled trials with novel hormonal therapies for non-metastatic castration-resistant prostate cancer: an update from mature overall survival data. Frontiers in oncology. 2021;11:700258.
  7. Chowdhury S, Oudard S, Uemura H, et al. Matching-adjusted indirect comparison of the efficacy of apalutamide and enzalutamide with ADT in the treatment of non-metastatic castration-resistant prostate cancer. Advances in therapy. 2020;37(1):501-511.
  8. Halabi S, Jiang S, Terasawa E, et al. Indirect comparison of Darolutamide versus Apalutamide and enzalutamide for nonmetastatic castration-resistant prostate Cancer. The Journal of Urology. 2021;206(2):298-307.
  9. Roumiguié M, Paoletti X, Neuzillet Y, et al. Apalutamide, darolutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer: a meta-analysis. Future Oncology. 2021;17(14):1811-1823.
  10. Wenzel M, Nocera L, Colla Ruvolo C, et al. Overall survival and adverse events after treatment with darolutamide vs. apalutamide vs. enzalutamide for high-risk non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Prostate cancer and prostatic diseases. 2022;25(2):139-148.

Read the Abstract