Ours is the first study to report that changing the treatment from a GnRH antagonist (degarelix) to a GnRH agonist did not affect the oncological outcomes in patients with hormone sensitive PCa. It is widely known that ADT is effective for the treatment of locally advanced PCa or metastatic PCa. As such, castration and GnRH agonist therapy remain the mainstream treatments for patients with advanced PCa. Results of the CS21 study  demonstrated that GnRH antagonists are effective in promptly reducing testosterone levels and suppressing the initial testosterone surge that is common in ADT. Therefore, results from the initial CS21 study with a 12-month follow-up, and its extended study to a 27.5-month follow-up , indicate that immediate disease control can be achieved with degarelix, a GnRH antagonist, which is comparable to that achieved with the use of GnRH agonists. However, long-term follow-up data on the clinical outcomes of degarelix use is not currently available. Furthermore, once stable disease status has been achieved, due to the negative effects of repeated monthly administration at the injection site, switching to GnRH agonists is common in patients with severe reactions to degarelix. The effects of this change in treatment on clinical outcomes have not been previously reported. These gaps in the current knowledge regarding the use of degarelix motivated us to conduct this study.
We report the first long-term survival data of degarelix. The 5-year overall and cancer-specific survival rates were high in both groups; 88.5% in the continued group and 95.0% in the changed group. Furthermore, considering the high Gleason score, serum PSA level, and high proportion of patients with metastatic PCa in our study group, degarelix in the treatment of PCa might be much more effective than expected. As a comparison, of the patients treated with ADT, Hinotsu et al. reported the following 5-year overall survival rates: 90% (stage II), 80% (stage III), and 60% (stage IV) .
It was obvious from this study that CRPC conversion took approximately 3–4 years, although it did not reach the median at the time of our data analysis. Few studies have reported on the time to CRPC in ADT. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study by Sweeney et al. reported a median time to CRPC of 11.7 months in patients treated only with ADT . Although baseline characteristics between our study cohort and the CHAARTED cohort were not equivalent, the differences in the time to CRPC might reflect the differences in the treatment of PCa between the two studies. In our study cohort, a majority of patients received antiandrogen drugs (bicalutamide 80 mg) in combination with degarelix. Akaza et al. reported a significant overall survival advantage favoring the use of combined androgen blockade (CAB) over GnRH agonist monotherapy (Cox regression analysis HR, 0.78) . Similarly, Klotz et al. evaluated the efficacy of combining CAB therapy with bicalutamide 50 mg using validated statistical methodology to combine the Prostate Cancer Trialists’ Collaborative Group meta-analysis data  with data from a phase 3 trial of two CAB regimens (GnRH agonist plus bicalutamide 50 mg versus GnRH agonist plus flutamide) . Their analysis demonstrated that the combination of CAB with bicalutamide 50 mg could reduce the risk of death by 20% compared with castration alone (HR, 0.80). In the CHAARTED study, the median overall survival was 13.6 months longer with ADT plus docetaxel than with ADT alone (57.6 months versus 44.0 months; HR for death in the combination group, 0.61; 95% CI, 0.47–0.80; P < 0.001). Recently, the addition of abiraterone acetate and prednisone to ADT has significantly increased the overall survival and radiographic progression-free survival in metastatic HSPC . Considering these data, it is likely that the overall survival can be extended with the use of ADT plus other drugs compared with GnRH antagonist/agonist monotherapy.
As previously described, continuous administration of degarelix is troublesome due to the adverse events (skin reaction at the injection site) and the frequency of hospital visits as degarelix is only available in 1-month doses. Therefore, it is common practice to change the treatment from degarelix to a GnRH agonist once a stable PCa status has been achieved. In their evaluation of the endocrine assessment of the gonadal axis in patients whose treatment was changed from a GnRH antagonist to GnRH agonist, Miyazawa et al. identified a testosterone surge in 8.3% of their study patients, with this surge being mild and of very short duration . Furthermore, Miyazawa et al. did not observe a significant change in PSA levels after changing to the GnRH agonist leuprolide, and no patients reported symptoms associated with a testosterone surge over the observation period. Based on their findings, they concluded that switching from degarelix to leuprolide (a GnRH agonist) appears to be a reasonable therapeutic option for patients with PCa. In our study cohort, the time to CRPC was comparable between patients in whom degarelix was continued and those in whom treatment was changed to a GnRH agonist, although the overall- and cancer-specific survival rates were statistically superior in those in whom treatment was changed. In agreement with Miyazawa et al., the change in ADT did not affect PSA and testosterone levels. Therefore, it is safe to conclude that switching from degarelix to a GnRH agonist is an effective treatment for PCa.
Assessment of ALP levels before and during PCa treatment might provide useful prognostic information, with ALP levels after 6 months of ADT being predictive of overall survival in patients with PCa [17, 18]. Fritz et al. reported that degarelix successfully reduced ALP levels and maintained ALP suppression, although leuprolide did not . Our study did not support this finding, with levels of ALP reduction achieved with degarelix being maintained after the change to a GnRH agonist in patients with PCa and bone metastasis. This result also confirms that switching from degarelix to a GnRH agonist does not affect the disease control.
This study is a retrospective study and, thus, has certain limitations, including a selection bias which might have influenced our results. Our observation period was different for patients who continued degarelix and those who switched. The relatively short period of observation, with few cases of death, particularly in the changed group, may have influenced our group comparisons of overall- and cancer-specific survival. Both localized PCa and metastatic cases were included in our study group. Localized PCa should first be treated using a local approach, prostatectomy, or radiation therapy. Hormone therapy may be used in selected cases, based on the treatment complications, age, and comorbidities, among other factors. Further studies are needed to clarify the outcomes of ADT in patients who actually require hormonal therapy.