A long ridge walk

James Fleck, MD, PhD: Anticancerweb 09 (07), 2021

The best treatment for metastatic castration-sensitive prostate cancer (m-CSPC) remains unclear. There is no one rule that fits all patients. In fact, there is a lot of heterogeneity in the clinical presentation of the disease, leading to a customized decision, often supported by shared decision-making. Historically, androgen-deprivation therapy (ADT) was used as an initial single-treatment for m-CSPC. More recently, a benefit has been reported with combined-treatment strategies. Four drugs compete to be used with ADT in the treatment scenario of m-CSPC, namely docetaxel, abiraterone, apalutamide and enzalutamide. Despite pharmacodynamics and pharmacokinetics differences, all four drugs have their efficacy supported by prospective randomized trials.  

Docetaxel is a second-generation drug derived from the needles of the European yew tree, with broad-spectrum antitumor activity. The main mechanism of action is the inhibition of cell proliferation. Docetaxel expresses high affinity for the microtubule binding site, promoting tubulin assembly and stabilizing the polymer against depolymerization, which impairs microtubule dynamics. This disruptive mechanism also affects cell apoptosis signaling pathways. Docetaxel interacts with the Bcl-2 gene family, promoting its phosphorylation and decreasing its action in delaying apoptosis. Abiraterone acetate reduces extragonadal androgen production through a potent, selective, and irreversible blockade of the cytochrome P450 alpha-hydroxylase enzyme. Both apalutamide and enzalutamide bind to the ligand-binding domain of the androgen receptor, blocking nuclear translocation, further inhibiting DNA binding and transcription. Apalutamide and enzalutamide have minor structural differences, which could be responsible for enzalutamide's lower undesirable immune response.

On January 14^th 2021, a systematic review and network metanalysis was published on JAMA Oncology comparing six different approaches for the treatment of m-CSPC. The data resulted from a pool of seven trials, involving 7287 patients. ADT was combined to one of the following drugs: docetaxel, abiraterona, apalutamide, enzalutamide, nonsteroidal antiandrogen and placebo / no treatment. Improvement in overall survival was observed with the addition of abiraterona (HR = 0.61), apalutamida (HR = 0.67) or docetaxel (HR = 0.79). Increase in radiographic progression-free survival was observed with the addition of enzalutamide (HR = 0.39), apalutamida (HR=0.48), abiraterona (HR = 0.51) or docetaxel (HR = 0.67). Serious adverse events (SAEs) were reported primarily with docetaxel, followed by a slight increase in SAEs with the use of abiraterone.

Illustration of the randomized prospective clinical trials using overall survival as the outcome, containing on the X axis the Hazard Ratio (HR) of the observed benefit and on the Y axis the median follow-up in months. The diameter of the spheres represents the relative dimensions of the median follow-up time in months reported in clinical trials. (Delta t = duration of follow-up, HR = Hazard Ratio)

Illustration of the randomized prospective clinical trials using radiographic disease-free survival as a surrogate, containing on the X axis the Hazard Ratio (HR) of the observed benefit and on the Y axis the median follow-up in months. The diameter of the spheres represents the relative dimensions of the median follow-up time in months reported in clinical trials. (Delta t = duration of follow-up, HR = Hazard Ratio)

Unfortunately, methodological limitations persist in the main clinical trials. The expected median survival for any effective combined-treatment for m-CSPC goes beyond 48 months and the reported median follow-up in the enzalutamide and apalutamide trials were only 14 months and 23 months, respectively. Use of outcomes based on a surrogate (radiographic progression-free survival) may not be translated into survival gain, especially when a sequential approach is made available. The metanalysis reported suboptimal data sharing and some concern in risk of bias within trials. It is a long ridge walk and the best recommendation will still relay on shared-decision making. In addition, ACER / QALY assessments, addressing the huge differences observed in drug costs, should be highly recommended.

Reference:

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8. Lin Wang, Channing J. Paller, Hwanhee Hong: Comparison of Systemic Treatments for Metastatic Castration-Sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis, JAMA Oncol 7(3):412-420, 2021