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  • br Importantly our findings provide evidence that intensi


    Importantly, our findings provide evidence that intensi-fication of treatment is necessary for patients with Gleason 9–10 disease, both because of its worse prognosis and potentially decreased survival benefit from ADT compared with Gleason 8 disease. Gleason 9–10 PCa harbors Gleason pattern 5 disease, which is less differentiated and more aggressive than the Gleason pattern 4 disease found in most Gleason 8 tumors, and may have developed mechanisms to escape the traditional androgen dependence of lower-grade tumors. Specifically, mechanisms of castration resistance include androgen receptor (AR) amplification and over-expression; AR mutations and splice variants; modifications to AR coregulators; and AR activation secondary to intratumoral steroidogenesis [26]. Moreover, AR expression and activity are upregulated following radiotherapy and associated with disease progression, and the benefit of ADT in the adjuvant setting is thought to derive from suppres-sing radiotherapy-induced upregulation of the AR pathway [27]. It may be that AR expression and activity are elevated to a significantly greater degree in Gleason pattern 5 disease than in lower-grade tumors.
    Novel antiandrogens, namely abiraterone [6], enzaluta-mide [7,13], and apalutamide [12], and docetaxel [9,10] have been shown to improve metastasis-free and OS in patients with castration-resistant PCa by circumventing some of these mechanisms of resistance [26]. In fitting with the hypothesis that Gleason pattern 5 disease has decreased sensitivity to ADT is our finding that Gleason 10 tumors, which have a greater component of Gleason pattern 5 disease than Gleason 9 tumors, derive a smaller OS benefit from the use of ADT compared with Gleason 9 PCa.
    Recent prospective evidence has indicated a possible benefit from abiraterone and docetaxel in the upfront management of high-risk localized and locally advanced PCa. Planned subgroup analysis of locally advanced and node-positive patients from the STAMPEDE phase 3 trial found that the addition of abiraterone to long-course ADT improved failure-free survival (hazard ratio [HR] = 0.21, 95% CI: 0.15–0.31) and possibly also OS (HR = 0.75, 95% CI: 0.48– 1.18), though the upper bound of the 95% CI was greater than
    OS (HR = 0.87, 95% CI: 0.69–1.09), although this result may become significant with further follow-up [14]. Because of these equivocal yet promising results, the oncology 6diazo5oxo-L-nor-Leucine has been rightfully reluctant to routinely adopt the use of either agent in addition to the standard of care, that is, long-course ADT in the initial management nonmetastatic Gleason 8–10 disease.
    However, due to its clinical aggressiveness and decreased survival benefit from ADT compared with Gleason 8 disease, Gleason 9–10 disease may be the group which would benefit the most from docetaxel or abiraterone. Therefore, we encourage the serious consideration of either docetaxel or abiraterone in the management of Gleason 9–10 PCa as well as continued evaluation of novel antiandrogens and cytotoxic chemotherapy agents for these patients in an effort to improve outcomes, including through participation in clinical trials (eg, NCT02446444). Notably, clinical trials of high-risk patients have historically considered Gleason 8–10 patients as a homogenous entity, whereas future studies examining the differential benefit of a particular therapy for Gleason 9–10 compared with Gleason 8 disease will need to prospectively stratify.
    Interestingly, the CIs of the AHR for Gleason 9 and particularly Gleason 10 patients were greater than those for Gleason 8 patients. This may be driven partially by the difference in the number of events, with the Gleason 10 groups experiencing only 211 deaths versus 1429 deaths for Gleason 9 and 1937 deaths for Gleason 8.
    A few limitations of our study should be discussed. First, the follow-up was relatively short; however, the aggressive nature of high-grade disease allowed us to detect a robust OS difference within the short follow-up. Second, no central pathology review was conducted as patient samples were not available to the investigators. Third, the NCDB does not provide information on the type of metastatic workup sepals each patient received.
    Fourth, the NCDB only provides information on whether a patient received hormone therapy but does not contain information on the type or duration of hormone therapy. Since National Comprehensive Cancer Network guidelines endorse the use of an LHRH agonist or antagonist but not antiandrogen alone as first-line ADT, the proportion of patients in the study cohort who received an LHRH agonist or antagonist should be high [28]. Furthermore, an analysis of the Surveillance, Epidemiology, and End Results-Medi-care database found that an alarming 15% of high-risk men aged 65 yr in the USA did not receive any ADT, which is similar to the rates of ADT use found in our study cohort, and that the adherence to long-course ADT ( 24 mo) is only 24% [29]. These rates may reflect provider and patient preference toward avoiding the many adverse effects of ADT, including a potential for increased cardiovascular morbidity and mortality [22] despite the well-documented survival benefit [1–3]. However, the duration of ADT was longer for patients with more aggressive disease, such as Gleason score of 9–10 compared with Gleason 8 [29]. Fifth, patients who received ADT likely had additional negative prognostic features not captured in the NCDB, such as higher PSA velocity.