**4. Patients and Methods**

The SEER\*Stat software was used to select all patients with de novo mPCa from the SEER Research Data 2000–2017 [20]. Patients were assigned to three cohorts based on the year of diagnosis (2000–2003: Cohort A; 2004–2010: Cohort B; 2011–2014: Cohort C). Patients with prostate cancer were identified using the codes for malignant adenocarcinoma (8140/3) and prostate gland (C61.9). Only patients with a single tumor in medical history were selected. Metastatic patients were identified using a combination of the American Joint Committee on Cancer (AJCC) classification from the 3rd and 6th editions. According to the November 2019 submission of SEER data, the study cut-off for survival data was 31 December 2017. In order to minimize potential bias related to different follow-up among the cohorts, the maximum follow-up was fixed to 5 years, and patients diagnosed from 2015 onwards were excluded. OS was defined as the time from mPCa diagnosis to death from any cause. CSS was defined as the time from mPCa diagnosis to death from prostate cancer. Patient age (SEER standard for survival in prostate cancer: 15–54, 55–64, 65–74, 75–84, 85+), race, year of mPCa diagnosis, metastatic stage, and outcome data were included in the case listing session of SEER\*Stat. The variables described were analyzed in univariate analysis using Kaplan–Meier curves and a log-rank test. A *p*-value ≤ 0.05 was considered statistically significant. Cox proportional hazards models were used to test the effects of covariates on OS and CSS. Only patients who had known values for the variables of interest were included. The chi-square statistic was applied to compare groups. The IBM software Statistical Package for Social Sciences (SPSS) Version 23 and RStudio Version 1.2.5001 were used for data analysis.

## **5. Conclusions**

Our large-scale, retrospective study suggested that the real-world OS and CSS have not drastically changed during the last two decades in patients with de novo mPCa diagnosed in the United States. The median OS of these patients remained poor and did not exceed 2.5 years. Although we acknowledge that several potential confounding factors have not been adjusted in our analysis, our study highlighted that a significant discrepancy might exist between the benefit observed in randomized trials and the real-world data. Several reasons might explain this discrepancy, such as a lack of access to cancer cares, patients' ineligibility or refusal of treatments, insurance issues, or intrinsic aggressiveness of de novo disease. However, given that patients were not allocated according to the receipt of specific treatments, our results should not be used to draw conclusions about the potential efficacy of systemic therapies.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2072-6694/12/10/2855/s1, Table S1: Baseline characteristics—contingency table; Table S2: multivariable model for OS in Cohorts B and C; Table S3: multivariable model for CSS in Cohorts B and C.

**Author Contributions:** Conceptualization, C.C.; methodology, D.O., A.R.; formal analysis, C.C., A.R., L.Z.; data curation, L.Z., C.M.; writing—original draft preparation, C.C., D.S.; writing—review and editing, P.B., C.M., E.C., E.Z., D.S.; supervision, F.B., D.O., E.C.; project administration, L.Z. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** C.C. is supported by an ESMO Clinical Research Fellowship (2019–2020). This work has been awarded with a Conquer Cancer Foundation of ASCO Merit Award at 2020 ASCO–GU.

**Conflicts of Interest:** E.Z.: advisory board from Janssen. E.C.: honoraria from Astellas Pharma, AstraZeneca, Bayer, Janssen-Cilag, Pfizer; consulting or advisory role from Astellas Pharma, Astra Zeneca, Bayer, Janssen, Merk; Research Funding from AstraZeneca (Inst), Bayer (Inst), Janssen (Inst); travel, accommodations, expenses from Astellas Pharma, Astra Zeneca, Bayer, Janssen, Roche. D.O.: honoraria from Astellas Pharma (Inst), Bayer, Janssen; consulting or advisory role from AstraZeneca (Inst), Bayer, Bayer (Inst), Clovis Oncology, Janssen, Janssen (Inst); research funding from Astellas Medivation (Inst), AstraZeneca (Inst), Bayer (Inst), Genentech/Roche (Inst), Janssen

(Inst), Pfizer (Inst), Tokai Pharmaceuticals (Inst); travel, accommodations, expenses from Astellas Pharma, Bayer, Ipsen, Janssen. The other authors have no conflicts of interest to declare.
