In this study, we mainly aimed to examine whether there is a difference between rPFS and OS of mCRPC patients treated with E and AA. In addition, we evaluated prognostic factors affecting rPFS and OS in this patient group. Although E was statistically significantly superior to AA in terms of rPFS and OS, it didn’t provide a significant reduction in death risk compared to AA. In all patients, being <75 years of age, PSA decline of <50% at 12 weeks of treatment were found to be poor risk factors for rPFS. In our study, rPFS and OS were 12 months and 20 months in the entire cohort, 15 months and 29 months in the E group, and 7 months and 16 months in the AA group, respectively (E vs. AA; p<0.001 for rPFS, p=0.027 for OS).
In the COU AA-301 study, AA treatment was compared with placebo in mCRPC patients in post-docetaxel setting. Median rPFS was 8.5 months at a follow-up period of 20.2 months, and median OS was 15.8 months at the final analysis in the AA group; both superior to placebo (HR: 0.65; p<0.001)4. In the COU AA-302 study (pre-docetaxel setting trial of AA) at the end of a follow-up period of 49.2 months, the median rPFS was 16.3 months in patients given AA, and median OS was 34.7 months and 30.3 months, in the AA and placebo groups, respectively (HR: 0.81, p=0.003)8. In our study, AA treatment given in post-docetaxel and pre-docetaxel setting revealed an rPFS of 5 months and 12 months, and an OS of 13 months and 24 months, respectively. The reason for the shorter rPFS and OS compared to the COU AA301 and 302 studies may be the shorter follow-up time in our study. Unlike the COU-AA-302 study, our patient population in the AA group included patients with visceral metastasis.
E was approved in August 2012, based on the phase III, randomized trial AFFIRM, including 1199 patients who were randomized to receive E or placebo prior CT. Median OS was 18.4 months in patients who received E and 13.6 months in patients who received placebo (HR, 0.63, p<0.001). The time to PSA progression was 8.3 vs. 3.0 months (HR, 0.25; P<0.001) and rPFS was 8.3 vs. 2.9 months in the E and placebo groups, respectively (HR, 0.40; P<0.001)9. E was approved to be used in the pre-docetaxel setting with the PREVAIL study, which was terminated early, as pre-docetaxel E treatment demonstrated a clear superiority in rPFS (20 months vs. 5.4 months) over placebo. In the placebo arm, 167 patients had crossed over to receive E. At a median follow-up of 69 months, median OS was 35.3 and 31.3 months in the treatment arm and placebo arm, respectively10. In our study, E given in post-docetaxel and pre-docetaxel settings revealed a rPFS of 11 months and 17 months, an OS of 26 months and 29 months, respectively. Although the median follow-up time was shorter when compared to the studies mentioned above, the results were consistent with the literature. Even, our post-docetaxel rPFS and OS were longer than the AFFIRM study.
Simon et al. compared first line AA, E and docetaxel activities in a multi-center, retrospective study of 1874 patients with mCRPC. The median time to progression in the AA, E and docetaxel groups was 9.6, 10.3, and 7.6 months, respectively; the median OS was 27.1, 27.1, and 27.9 months, respectively11. In our study, rPFS was 12 and 17 months in the AA and E groups, and the median OS was 24 and 29 months, respectively. Oyman et al. retrospectively evaluated CT-naive and post-CT mCRPC patients who received AA. Median rPFS was 10.1 months in all patients, 10.1 months in the CT-naive group, and 9.7 months in the post-CT group (p=0.808). The median OS was 17.3 months in all patients, 12.7 months in the CT-naive group, and 29.4 months in the post-CT groups (p=0.236). While the numerical superiority in the results of our study was in patients who received pre-CT AA, the results of Oyman et al. were in favor of post-CT AA12. Marret et al. evaluated the efficacy of AA in 93 patients with mCRPC; the median duration of treatment with AA was 12.7 months and 7.5 months; median OS was 36.4 months and 13.4 months in pre-docetaxel (n=33) and post-docetaxel (n=58) settings, respectively. Similar results were obtained in our study13. Another real-world study evaluated 110 patients with mCRPC who were treated with AA. Of the patients, 58 and 52 received AA in prechemotherapy (preCT) and postchemotherapy (postCT) settings, respectively. Median PFS was 15.5 and 6.4 months, and OS was 18.1 and 6.7 months for preCT and postCT groups, respectively. Similar to our study, the factor affecting PFS and OS was a decline of> 50% in PSA levels in the first 3 months. Survival was significantly lower in patients with visceral metastasis14.
Nadal et al. examined 107 patients who were treated with E. Of the patients, 60 were pretreated with docetaxel and 47 were docetaxel-naive. Median PFS was superior in the docetaxel naive group (p<0.0001). They claimed that E activity was lower in patients who had previously received docetaxel CT and thought that there might be cross resistance between docetaxel and E. The follow-up period in the study of Nadal et al. was shorter than that in our study15. In a Japanese retrospective study about the treatment efficacy, safety profile, and prognostic factors of E, 184 patients with non-mCRPC and mCRPC were analyzed; 44 (23.9%) non-mCRPC patients, 89 (48.4%) docetaxel-naive mCRPC patients, and 51 mCRPC patients pretreated with docetaxel (27.7%) mCRPC patients underwent E therapy. The median PSA PFS was 16.5 and 7.0 months, and overall survival was 59.8 and 30.4 months for docetaxel-naive and for docetaxel-pretreated mCRPC patients, respectively. Multivariate analysis identified that the predictive factor for a shorter OS was 4-week PSA decline <50%. This study had a relatively longer observation period with a median follow-up of 41.3 months, than the other retrospective studies and our study16.
The other retrospective studies comparing E and AA in a design similar to our study were reviewed. Al-Ali et al. analyzed 457 patients with CRPC who received AA and/or E in preCT and postCT settings. The median OS of the entire cohort was 21 months, 15 months for the AA group, 24 months for the E group, 26 months for the sequence group, and 10 months for the sequence group after switching. Median OS in the pre-CT setting was 25 months (mean: 21.5 ± 1.1 months) in the entire cohort, 18 months in AA group (mean: 18.9 ± 1.5 months) and 17 months in E treatment group (mean: 18.2 ± 1.9 months). In the post-CT setting, the median OS was 14 months in the AA group (mean: 15.8 ± 0.9 months), 19 months in the E group (mean: 17.2 ± 1.4 months) and 25 months in the sequence group (mean: 22.7 ± 0.8 months)17. In the study of Al-Ali et al., OS was shorter than our study and the other pilot studies in mCRPC patients treated with AA and E. Miyake et al compared the efficacy of AA and E in mCRPC patients in pre-CT setting. The study included 280 mCRPC patients, of the patients 113 and 167 were receiving AA and E, respectively. In the E group, PSA response rate and PSA PFS were significantly higher than that in the AA group. Duration of ADT treatment and ECOG PS for the AA group, age and ECOG-PS for the E group, and ECOG-PS for the overall patients were identified as the independent predictors of PSA PFS. The rate of patients with grade ≥ 3 side effects in the E group (11.4%) was significantly higher than that in the AA group (4.4%)18. In a meta-analysis, Wang et al. compared the clinical efficacy and safety of AA and E in mCRPC patients on the results of 14 cohort studies including 3469 patients. Pooled results demonstrated that E was more effective than AA for patients with mCRPC, however was related with a significantly elevated risk of side effects, particularly fatigue. Comparisons for PFS were mentioned in 3 studies (n=386) and comparisons for OS in 4 studies (n=774)19. Similar to our results Miyake et al. found a significant difference in PFS between E and AA treatment in docetaxel-naive mCRPC patients (median PFS, E vs. AA; 11.6 vs. 9.0 months, p=0.014). Additionally, in 4 studies, the two drugs were not different in terms of OS. Norris et al. compared mCRPC patients treated with AA or E. Similar to our study, more patients in the E (51%) than the AA (36%) group had a >50% PSA decline (p=0.031). However, there was no significant difference between the two groups in terms of OS (OS was 15.3 months vs. 22.2 months, AA vs. E, p=0.913) and in the time-to-treatment failure (p=0.464)20.
Due to the shorter follow-up time compared to other studies, rPFS and OS were relatively shorter in our study when compared to the results of other E and AA studies. Our study was retrospective, but as the patient groups had similar clinicopathological features, the results can be used to compare the efficacy of the two drugs in mCRPC patients. There is currently no prospective study in the literature similar to the design of this study. We suggest that the reasons why E was found to be significantly superior to AA in terms of rPFS and OS, were that the rate of metastasis at the time of diagnosis was significantly higher in the AA group (E vs. AA, 55.6 vs. 71.1 p=0.016) and the PSA decline rates were lower in the AA group. When the PSA decrease rates were examined, it was found that only ≥50% PSA decrease in the AA group had a significant effect on both rPFS and OS. In the real-world studies performed with E, the most noticeable side effect was fatigue, which was higher than that found in phase 3 prospective trials. Since our study lacked side effect data, we could not give any results on this topic.
With the recent use of E and AA in hormone sensitive patients, the question is whether our real-world data will be compatible with the results of randomized prospective studies in the literature. Therefore, real-life parameters affecting rPFS and OS in our study and other retrospective studies will guide us to discover new indications for these drugs.