Degarelix Therapy for Prostate Cancer in a Real-world Setting

Experience From the German IQUO (Association for Uro-Oncological Quality Assurance) Firmagon Registry

Götz Geiges; Thomas Harms; Gerald Rodemer; Ralf Eckert; Frank König; Rolf Eichenauer; Jörg Schroder

Disclosures

BMC Urol. 2015;15(122) 

In This Article

Discussion

Patient registries offer a unique and powerful tool for the collection of observational and clinical data, helping provide a clearer understanding of a therapy's impact on patients in a real-world context. While patient populations in clinical trials are tightly controlled, with rigorous selection criteria, registries generally have much broader inclusion criteria and fewer exclusion criteria which can lead to greater generalizability.[11]

Degarelix is a GnRH antagonist for the first-line treatment of androgen-dependent advanced PCa. However, comparison of patient populations in the Firmagon registry versus clinical trials shows that while degarelix trials excluded patients with previous hormonal management of PCa (except those who underwent localized therapy of curative intent in which neoadjuvant or adjuvant HT for ≤ 6 months was accepted),[1,3,12,13] over half the patients in the current registry had received prior HT (30 % of the total population had received prior LHRH agonists). It was observed that, in this study of real-world experience with degarelix therapy, of those with documented answers, degarelix was discontinued in 30.7 % of patients due to a change in therapy and in 22.8 % as a result of patient request/other reasons compared with 14.4 % of patients discontinuing due to PSA progression and 7.5 % due to clinical progression. Information regarding the reasons for patients changing therapy was not collected in the current analysis; reasons for changing treatment may possibly include higher expectations regarding efficacy and/or lowering side effects.

Also, 34 % of the registry population had baseline metastastic disease compared with around 20 %[1,12,13] to 23 %[3] in clinical trials. Interestingly, in our registry, 46 % of patients who received degarelix had localised disease and over half had PSA ≤20 ng/mL. In the community setting, ADT has been used commonly as primary therapy for localised prostate cancer[14] particularly in the elderly.[15] However, European Association of Urology guidelines consider androgen suppression to be unsuitable as primary therapy for low-risk prostate cancer and consider that, in patients with non-metastatic localised disease not suitable for curative treatment, immediate ADT should be used only in patients requiring symptom palliation.[16]

In the current study, degarelix achieved a complete response in 20 % of patients after 1 year and 19 % after 2 years; although this value rose to 35 % at 3 years, patient numbers at this time were small. Partial responses were noted in 20 %, 22.5 % and 17 % of patients, after 1, 2 and 3 years, respectively. In the degarelix trial of Ozono et al.,[3] the best overall response (complete response [3.6 %] + partial response [67.9 %]) was 71.4 % in the 240/80 mg group.

In our registry study, patients with prior HT appeared to have a significantly higher mortality risk (hazard ratio 1.58) compared with those who had not received prior HT. Castration resistance and concomitant progression is inevitable in these patients and it is not surprising that prior HT shortens the observed remission time for every other androgen deprivation therapy, such as degarelix, that commences thereafter. Also, in the subgroup who had received prior LHRH analogues (LHRH agonist/GnRH antagonist), the 75th percentile value for OS was shorter than in those not pre-treated with LHRH analogues. Similarly, a higher percentage of patients who had received prior LHRH analogues experienced PSA progression compared with those who had not, and median time to PSA progression was shorter (209 weeks) in the subgroup who had received prior LHRH analogues versus those who had not (median PSA PFS not reached). These results appear to compare favourably with earlier studies of ADT. One large study of ADT in previously untreated PCa patients showed a median PFS of 16.5 months and 13.9 months, with LHRH agonists with and without antiandrogen, respectively.[17] In other studies in previously hormone-naïve patients, similar times to progression have been noted with LHRH agonists with/without antiandrogens (in the range of 12 to 23 months).[18–22]

Data from clinical studies show that degarelix displayed superior PSA PFS compared with leuprolide over 1 year,[6] and there was an improvement in PSA PFS in patients who crossed over from leuprolide to degarelix in a long-term extension trial.[2] Furthermore, a pooled analysis also showed improved PSA PFS and longer OS (likely due to a decreased risk of cardiovascular disease) with degarelix compared with LHRH agonists.[23] Indeed, compared to LHRH agonists, GnRH antagonists appear to halve the number of cardiac events experienced by men with pre-existing cardiovascular disease during the first year of ADT.[24] Improvements in PSA PFS are indicative of delayed progression to castration-resistant disease with degarelix. Interestingly, since over half of the registry patients had received prior HT, it was not expected to achieve the same efficacy as in controlled studies which generally excluded patients who had prior HT. Nevertheless, the current registry data indicate that degarelix provides some benefit in patients who were pre-treated with HT (e.g. LHRH-agonists), while most benefit was observed in hormone-naïve patients.

PSA suppression in registry patients with no prior HT was more rapid and effective than those pre-treated with HT; moreover, the hormone-naïve cohort showed a PSA suppression profile similar to that observed with degarelix in clinical trials where previous hormonal management of PCa was excluded.

In the registry patients, PSA reduction to ≤ 4 ng/ml was achieved in 65 % of patients at 12 months and 71 % at 24 months. In the pivotal phase III degarelix clinical trial (CS21), the proportion of patients achieving PSA suppression < 4 ng/ml was 83 % after 1 year.[6] The difference most likely reflects the fact that patients in the registry had a higher risk compared to the registration trial, CS21. Over time, the proportion of registry patients with metastatic disease who achieved PSA suppression < 4 ng/ml was lower than the overall registry population; similarly, the proportion of patients with metastatic disease in the CS21 trial achieving PSA suppression < 4 ng/ml was also lower than the overall study population. Southwest Oncology Group trial S9346 data showed that PSA ≤ 4 ng/ml after ADT is a strong predictor of survival.[25] After controlling for prognostic factors, patients with PSA ≤ 4 to > 0.2 ng/ml had less than one-third the risk of death versus those with PSA > 4 ng/ml; median survival was 13 months for patients with PSA > 4 ng/ml versus 44 months for patients with PSA > 0.2 to ≤ 4 ng/ml.

The registry data also showed that overall, degarelix produced a rapid and profound testosterone suppression that was sustained for up to 24 months. Testosterone was also suppressed in patients with baseline metastatic disease. Testosterone measurement was optional and so, over time, patient numbers were small.

S-ALP is a marker of bone formation and baseline levels are high in metastatic disease, indicative of skeletal metastases.[7] Therefore, we examined the effect of degarelix in the cohort of patients with metastatic disease and found that S-ALP was suppressed after 6–12 months with degarelix. This compares with S-ALP suppression below baseline levels in the metastatic cohort after only 2 months of degarelix therapy in the CS21 trial.[7] A decrease in bone turnover marker levels may delay progression of bone metastases and improve survival.

Neo-adjuvant ADT can reduce prostate volume before radiotherapy. The registry data showed a decrease in prostate volume of almost 18 % at 3 months (and ~28 % at 6 months). This is slightly below the reported reductions (37–42 %) in prostate volume achieved with degarelix in clinical studies.[26,27] As well as facilitating more effective delivery of radiotherapy, rapid and pronounced reduction of total prostate volume may also provide additional benefit for patients with obstructive lower urinary tract symptoms.

Degarelix was well tolerated in registry patients, with similar adverse event profiles for patients at the first and last data points. Moreover, the adverse event profile (based on adverse events at the last data point) was as expected for this patient population and similar to that of patients receiving degarelix in the 1-year phase II and III clinical trials, with the most frequent adverse events typically comprising injection-site reactions, hot flushes, and fatigue.[1,12,13]

Some limitations of registry-based cohort studies may include limited availability of treatment data and underreporting of outcomes if a patient leaves the registry or is not adequately followed up.[11] In the current registry, over time, patient numbers for some parameters (especially e.g. testosterone, prostate volume, and S-ALP where recording was optional) became quite small in some patient subgroups (e.g. metastatic patients) which may affect the reliability of measurements towards the end of the observation period in these cases. Missing data are a common phenomenon in healthcare research projects; not all data provided are complete due to the non-interventional nature of this study type. The uncertainty based on this will be relativized by the collection and generation of more data. Where there is a significant quantity of missing data, this may bias or impact on the study finding. One reason for the reduced number of patients is that some patients at the time of the analysis had not yet reached the full follow-up period.

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