
==== Front
J Cancer Res Clin Oncol
J Cancer Res Clin Oncol
Journal of Cancer Research and Clinical Oncology
0171-5216
1432-1335
Springer Berlin Heidelberg Berlin/Heidelberg

39249593
5928
10.1007/s00432-024-05928-7
Research
Apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC): real world data of a multicenter study
Hegele Axel lexaelegeh@aol.com

12
Häußermann Rainer 12
Schultheis Stefan 3
Skrobek Lennart 4
Vink Meike 5
Hollwegs Sebastian 6
Ludwig Martin 7
Huwe Petra 8
Maywurm Manfred 9
Bartsch-Polle Anke 6
Weber Jost 4
Thiemer Markus 10
Varughese Denny 3
1 Urological Center Mittelhessen, DRK Hospital Biedenkopf, Biedenkopf, Germany
2 https://ror.org/01rdrb571 grid.10253.35 0000 0004 1936 9756 Department of Urology, Philipps University Marburg, Marburg, Germany
3 Urologen am Ludwigsplatz, Giessen, Germany
4 Urological Center Wetterau, Büdingen, Germany
5 Urological Practice, Homberg/Efze, Germany
6 UroFaz, Wetzlar, Germany
7 Urological Center Marburg, Marburg, Germany
8 Urological Practice, Giessen, Germany
9 Urological practice clinic Marburg, Marburg, Germany
10 https://ror.org/01rdrb571 grid.10253.35 0000 0004 1936 9756 Department of Radiotherapy and Radiooncology, Philipps-University Marburg, Marburg, Germany
9 9 2024
9 9 2024
2024
150 9 41431 5 2024
16 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose

Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nevertheless real-world data are limited. The aim of this multicenter study was to generate real-world data from nmCRPC patients treated with ADT plus apalutamide.

Methods

In this observational cohort based investigator initiated trial data of nmCRPC patients receiving apalutamide plus ADT were collected focusing on patient demographic data, prostate-specific antigen (PSA) declines, safety profile including dose modification/discontinuation as well as subsequent therapy and metastasis-free survival (MFS).

Results

Data from a total of 31 nmCRPC patients were documented. Compared to the Phase III study Spartan real-world patients are older, showed a higher ECOG-PS and more aggressive tumors. In the cohort PSA decreased about 98.1%, 74% of patients showed a PSA decrease over 90% and 54.8% reached a PSA-level < 0.2ng/ml. Apalutamide was well tolerated in real world patients: adverse events occurred in 67.7% but were in the majority mild (≥ grade 3: 6.5%). Dose reduction was necessary in 38.7% and 32.2% discontinued apalutamide treatment. MFS was 43 months and majority of patients were subsequently treated with abiraterone.

Conclusion

In real world more comorbid nmCRPC patients with a higher ECOG-PS and more aggressive tumors are treated with apalutamide plus ADT. Nevertheless efficacy results as well as side effects are similar in real-world compared to Spartan trial showing also a rapid, durable and deep PSA response with a median MFS of 43 months.

Keywords

Real-world data
Non-metastatic castration-resistant prostate cancer
Apalutamide
Metastasis-free survival
Philipps-Universität Marburg (1009)Open Access funding enabled and organized by Projekt DEAL.

issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) without further treatment are developing metastases associated with significant morbidity and mortality despite ongoing androgen-deprivation therapy (ADT) (Scher 2015, Crona 2017; Smith 2011). A short PSA doubling time (PSADT) ≤ 10 months and a PSA-level ≥ 8ng/ml may help to identify nmCRPC patients who were at high risk for disease progression (Smith 2011 and 2013). In 2018 the Phase III trial Spartan showed that the oral non-steroidal anti-androgen apalutamide increased metastasis-free survival (MFS) as well as overall survival (OS) in high-risk nmCRPC patients compared to placebo leading to approval of apalutamide for patients with high-risk nmCRPC (Smith 2018 and 2021). Apalutamide binds directly to the ligand-binding domain of the androgen-receptor (AR) thus preventing AR translocation, DNA binding and transcription mediated by AR (Clegg 2012). Results of randomized clinical trials (RCT) represents the highest level of evidence (Dahm 2020). Nevertheless RCTs have limitations – most notably used inclusion criteria often do not reflect real-world patient population. Elderly and more comorbid patients were common especially in cases of prostate cancer. To date patients of this type are often underrepresented or even not represented at all in clinical trials. So real-world data adding valuable data to the information obtained from RCTs are of high interest (Schad 2022; Baumfeld 2020). The aim of our study was to generate real-world data in nmCRPC patients treated with apalutamide in daily practice concerning patient population, used imaging tools, efficacy, safety as well as dosage-changes and subsequent therapy.

Materials and methods

This study (Use of Apalutamide in prostate cancer in Central Hessen: AmPel) is an observational retrospective cohort based investigator initiated trial (IIT) with focus on real world evidence. The study was performed from November 2021 (ongoing) in nine urological practices in the middle of Hessen/Germany. Patients who started apalutamide therapy due to nmCRPC were added and followed as commonly done in each practice without a universal protocol and specifications concerning imaging controls and time intervals.

The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the Philipps University Marburg, Medicine school (authorization number: 163/21).

Patients data included age, time of follow-up, ECOG performance Score (ECOG PS), date of initial prostate-cancer diagnosis, Gleason-Score, initial PSA-level, prior cancer-specific treatment, time to castration resistance, PSADT as well as used imaging method.

Efficacy variables included PSA levels prior start of apalutamide treatment (baseline) and during treatment – normally all 3 months like it was performed routinely in the participating urological practices. Decrease of PSA levels after time and best achieved individual percentage PSA-decrease (≥ 50% PSA reduction, ≥ 90% PSA reduction) as well as patient reaching a PSA ≤ 0.2ng/ml were estimated.

Discontinuation of treatment due to various reasons (progression, toxicity, patients request) and subsequent therapies were documented. MFS was calculated.

Safety variables were the type of adverse event (AE) and the respective grade according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).

Data were collected and analyzed using Excel for Windows (Version 2013). Kaplan Meier survival analysis on MFS was performed with Graphpad Prism 9.5.1.

Results

Patients

In this ongoing IIT data was analyzed in a total of 31 nmCRPC patients and documented from November 2021 until November 2023. These patients were included in 9 urological practices in Hessen/Germany. 39.1% of the patients underwent previous prostate cancer treatment (prostatectomy, radiation). The median PSA-level before starting apalutamide therapy was 7.21 ng/ml, median PSA doubling time (PSADT) was 4 months and 81.5% showed a PSADT ≤ 6 month. All patients started with the full apalutamide dosage of 240 mg daily. Median follow-up was 18 months (range 3–50). Median time to castration resistance was 72 months (range 12–264). Patients and disease characteristics before starting apalutamide treatment are summarized in Table 1 in comparison to the pivotal trial Spartan (Smith 2018).

Table 1 Characteristics of nmCRPC patients compared to spartan trial

	AmPel trial	Spartan trial	
Number of patients [n]	31	806	
Median FU [months]	18	20.3	
Median age [years, range]	78 (56–89)	74 (52–97)	
ECOG PS [%]			
0	29.6	77.3	
1	40.7	22.7	
2	25.9	0	
3	3.7	0	
Previous cancer treatment [%]			
Prostatectomy/Radiation	39.1	76.6	
Gleason Score [%]			
< 7	10.5	19.4	
= 7	31.6	37.1	
> 7	57.9	43.5	
Diagnostic technique [%]			
Conventional imaging	96.8	100	
PSMA-PET/CT	3.2	0	
PSA doubling time (months)			
Median	4.0	4.4	
≤ 6 months [%]	81.5	71.5	
> 6 months [%]	18.5	28.5	
median PSA baseline [ng/ml]	7.21	7.78	

Efficacy

PSA response of the cohort was observed at all time points. PSA of the cohort decreased about 91.3%, 95% and 98.1% after 3 months, 6 months and 9 months, resp. (see Fig. 1). Additional individual PSA reduction of ≥ 90% and ≥ 50% was achieved after 3 months in 74.2% and 90.3% of the patients resp. Initial PSA progression was seen in only 3.2%. PSA level decreased ≤ 0.2 ng/ml in 54.8% of patients after 3 month (see Fig. 2). During treatment 19.4% of patients showed progression to metastatic disease resulting in a median MFS of 43 months (see Fig. 3).

Fig. 1 Median PSA levels of the cohort at different time points after starting apalutamide treatment showing a rapid and durable PSA response

Fig. 2 Number of patients [%] who achieved decreased PSA-levels ≥ 50%, ≥ 90% and PSA increase (blue bars) after 3 months. Yellow bar show the number of patients [%] with PSA decrease ≤ 0.2 ng/ml

Fig. 3 Median metastasis-free survival (MFS) was 43 months

Safety and subsequent therapy

In 32.3% of the patients no adverse events were documented. In 67.7% of the patients any adverse event, but only in 6.5% of them an adverse event grade ≥ 3 occurred. No death occurred. Table 2 presents a summary as well as most frequent types of adverse events. In 38.7% of the patients apalutamide dose reduction was necessary due to toxicity. 32.3% of the patients discontinued apalutamide treatment due to any reason: progression to metastatic disease was observed in 19.4%, toxicity in 6.5% and patients request in 9.7%. After discontinuation of apalutamide treatment due to progression 12.9% received abiraterone and 3.2% radiation therapy only. In 6.5% therapy was switched to enzalutamide due to toxicity.

Table 2 Summary of adverse events (AE) in general and the most frequent AE´s

	Patients with AE	Rash	Fatigue	Hot flash	Fall	Dizziness	
all grades [%]	67.7	16.1	12.9	9.7	6.5	6.5	
grade ≥ 3 [%]	6.5	3.2	3.2	0	0	0	

Discussion

Non-metastatic castration-resistant prostate cancer (nmCRPC) frequently advances to metastatic disease associated with poor clinical outcome as well as reduction of quality of life (Smith 2005 and 2011, Rönningas 2022). Recently the phase III trial Spartan demonstrated that apalutamide a novel receptor axis-targeted agent significantly improved metastasis-free survival (MFS) as well as overall survival (OS) in nmCRPC patients compared to placebo (Smith 2018 and 2021). However, due to lack of evidence it remains unclear if apalutamide in real-world clinical practice also results in improved outcome.

In our multicenter real-world study there are some important demographic differences: compared to Spartan trial our nmCRPC patients showed a higher ECOG PS (> 70% ≥ ECOG PS 1) and nearly 30% of the cohort a ECOG PS ≥ 2. Especially this patient group is even not included in the Spartan trial (Smith 2018). In addition real-world patients showed a higher proportion of high-grade Gleason score (57.9% vs. 43.5%) as well as PSADT ≤ 6 months (81.5% vs. 71.5%). Similar differences were described by Sánchez JC et al. (2023) in a smaller real-world nmCRPC cohort (n = 18). In Spartan trial number of pre-treated patients were nearly doubled compared to our cohort, maybe explained by the larger number of patients. In both real-world and Spartan trial conventional imaging was performed in about 55% of the patients (Smith 2018). Nowadays there is a broader availability of PSMA-PET/CT as preferred and guideline-recommended staging imaging tool in nmCRPC reaching almost 100% detection rate of metastases. So using PSMA-PET/CT routinely therapy modalities of nmCRPC will change in the near future (Fendler 2019, Baboudjian 2022).

Our real-world cohort showed a rapid and durable PSA response. Median PSA levels of the cohort are decreasing with the lowest level after 9 months (0.1ng/ml). After 3 months a PSA reduction ≥ 90% and ≥ 50% was achieved in 74.2% and 90.3% resp. Deep PSA response reflected in a PSA-level ≤ 0.2ng/ml was obtained in 54.8% in real-world setting. Our data are in line with Spartan trial showing a PSA decrease ≥ 90% in 62% but a lower level of patients reaching PSA ≤ 0.2ng/ml (34%) despite higher percentage of PSADT ≤ 6months and high-grade Gleason score in our cohort. Nevertheless MFS was 43 months in our real-world cohort and comparable to the pivotal trial (40.5 months) (Smith 2018, Saad 2022).

Apalutamide treatment was also safe in real-world use. The documented overall AE rate (67.7%) as well as AE ≥ 3 (6.5%) was distinct lower compared to Spartan trial (96.5%, 45.1% resp.). In clinical trials reporting of AE´s are more strict and detailed compared to real-world practice (Eichler 2021). Additional patients maybe consult directly the specialist of the affected organ e.g. dermatologist in case of rash (Katsuta 2024). So the AE differences are not surprising and are in line with other real-world data (Sánchez JC 2023, Hussain 2022). Nevertheless beside the known and described side effects of apalutamide like rash and fatigue about 10% of the real-world patients mentioned hot flashes. In Spartan trial incidence of hot flashes are not reported as frequent side effect (> 15%) or adverse events of interest. Only a small number of patient (0.5%) in Spartan trial discontinued apalutamide therapy due to hot flashes (Smith 2018). Our data clearly identify the higher incidence and severity of hot flashes in a real-world population and should be considered when treating nmCRPC patients with apalutamide. Discontinuation of apalutamide treatment in real-world was also similar to Spartan trial (32.2% vs. 39.1%) as well as nmCRPC patients with disease progression (19.4% vs. 19.3%). Apalutamide dosage was reduced in 38.7% due to toxicity – reflecting the higher ECOG PS with more comorbidities however reaching satisfactory treatment efficacy.

Subsequent therapy in case of progression was abiraterone acetate (plus prednison) similar to the Spartan population. Another real-world study focusing ADT/apalutamide in nmCRPC patients (n = 18) used predominantly taxan-based chemotherapy (Sánchez JC 2023). This might depend on local reimbursement modalities and therapy restrictions. If AE´s were the reason for discontinuation a second hormonal agent was preferred because changing mode of action was not meaningful and other potential agents could be reserved for future use.

However our results are in line with the pivotal trial but there are several limitations of our real-world study. The small number of patients reflecting the increasing use of PSMA-PET/CT in the event of rising PSA-levels as well as the short follow-up. In Spartan trial the number of pre-treated patients were nearly doubled compared to our real-world cohort hamper the comparability of the findings. Another limitation is the missing standard of imaging to assess metastatic disease under treatment illustrating the typical limitations of real-world studies beside for instance medical records with unavoidable lack of data especially in a multicenter setting.

In conclusion in this largest nmCRPC real-world cohort more comorbid patients with a higher ECOG PS – not included in clinical trials- and more aggressive tumors were treated with apalutamide. Nevertheless efficacy results as well as adverse events are consistent with data of the phase III trial Spartan showing a rapid, durable and deep PSA response with similar MFS. As a matter of fact in real-world hot flashes are a clinical relevant and notable side effect.

Acknowledgements

The help of Joerg Haenze and Marc v. Itter is gratefully acknowledged.

Author contributions

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.Financial interests: Axel Hegele recieved speaker and consultant honoraria from Janssen/germany. All other authors have no relevant financial or non-financial interests to discloseAxel Hegele contributed to the study conception and design. All authors performed data collection. Material preparation, data summarizing and analysis were performed by Axel Hegele and Denny Varughese. The first draft of the manuscript was written by Axel Hegele and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Data availability

The data cannot be shared openly. Data of the findings have been deposited on the server of Urological Center Mittelhessen and can be aprehended after contacting the corresponding author.

Declarations

Competing interests

The authors did not receive support from any organization for the submitted work. Axel Hegele has received speaker and consultant honoraria from Janssen (Germany) and served on advisory boards for Janssen (Germany). All other authors have no relevant financial or non-financial interests to disclose.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

Baboudjian M, Gauthé M, Barret E, Brureau L, Rocchi P, Créhange G, Dariane C, Fiard G, Fromont G, Beauval JB, Mathieu R, Renard-Penna R, Roubaud G, Ruffion A, Sargos P, Rouprêt M, Ploussard G (2022) How PET-CT is Changing the Management of Non-metastatic Castration-resistant Prostate Cancer? Comment la TEP-TDM Peut Modifier la Prise en Charge du Cancer de la Prostate Non Métastatique Résistant à la Castration ? Prog Urol 32:6S43-6S53. 10.1016/S1166-7087(22)00174-9
Baumfeld Andre E Reynolds R Caubel P Azoulay L Dreyer NA Trial designs using real-world data: the changing landscape of the regulatory approval process Pharmacoepidemiol Drug Saf 2020 29 1201 1212 10.1002/pds.4932 31823482
Baumfeld Andre E, Reynolds R, Caubel P, Azoulay L, Dreyer NA (2020) Trial designs using real-world data: the changing landscape of the regulatory approval process. Pharmacoepidemiol Drug Saf 29:1201–1212. 10.1002/pds.493231823482 10.1002/pds.4932
Clegg NJ Wongvipat J Joseph JD Tran C Ouk S Dilhas A Chen Y Grillot K Bischoff ED Cai L Aparicio A Dorow S Arora V Shao G Qian J Zhao H Yang G Cao C Sensintaffar J Wasielewska T Herbert MR Bonnefous C Darimont B Scher HI Smith-Jones P Klang M Smith ND De Stanchina E Wu N Ouerfelli O Rix PJ Heyman RA Jung ME Sawyers CL Hager JH ARN-509: a novel antiandrogen for prostate cancer treatment Cancer Res 2012 72 1494 1503 10.1158/0008-5472.CAN-11-3948 22266222
Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH (2012) ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 72:1494–1503. 10.1158/0008-5472.CAN-11-394822266222 10.1158/0008-5472.CAN-11-3948
Crona DJ Whang YE Androgen receptor-dependent and -independent mechanisms involved in prostate Cancer Therapy Resistance Cancers (Basel) 2017 9 67 10.3390/cancers9060067 28604629
Crona DJ, Whang YE (2017) Androgen receptor-dependent and -independent mechanisms involved in prostate Cancer Therapy Resistance. Cancers (Basel) 9:67. 10.3390/cancers906006728604629 10.3390/cancers9060067
Dahm P Kunath F Evidence-based medicine in urology World J Urol 2020 38 515 516 10.1007/s00345-020-03139-6 32112241
Dahm P, Kunath F (2020) Evidence-based medicine in urology. World J Urol 38:515–516. 10.1007/s00345-020-03139-632112241 10.1007/s00345-020-03139-6
Eichler HG Pignatti F Schwarzer-Daum B Hidalgo-Simon A Eichler I Arlett P Humphreys A Vamvakas S Brun N Rasi G Randomized controlled trials Versus Real World evidence: neither Magic nor myth Clin Pharmacol Ther 2021 109 1212 1218 10.1002/cpt.2083 33063841
Eichler HG, Pignatti F, Schwarzer-Daum B, Hidalgo-Simon A, Eichler I, Arlett P, Humphreys A, Vamvakas S, Brun N, Rasi G (2021) Randomized controlled trials Versus Real World evidence: neither Magic nor myth. Clin Pharmacol Ther 109:1212–1218. 10.1002/cpt.208333063841 10.1002/cpt.2083
Fendler WP Weber M Iravani A Hofman MS Calais J Czernin J Ilhan H Saad F Small EJ Smith MR Perez PM Hope TA Rauscher I Londhe A Lopez-Gitlitz A Cheng S Maurer T Herrmann K Eiber M Hadaschik B Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer Clin Cancer Res 2019 25 7448 7454 10.1158/1078-0432.CCR-19-1050 31511295
Fendler WP, Weber M, Iravani A, Hofman MS, Calais J, Czernin J, Ilhan H, Saad F, Small EJ, Smith MR, Perez PM, Hope TA, Rauscher I, Londhe A, Lopez-Gitlitz A, Cheng S, Maurer T, Herrmann K, Eiber M, Hadaschik B (2019) Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer. Clin Cancer Res 25:7448–7454. 10.1158/1078-0432.CCR-19-105031511295 10.1158/1078-0432.CCR-19-1050
Gartrell BA, Coleman R, Efstathiou E, Fizazi K, Logothetis CJ, Smith MR, Sonpavde G, Sartor O, Saad F (2015) Metastatic prostate Cancer and the bone. Significance and Therapeutic Options. Eur Urol 68:850-858. doi:10.1016/j.eururo.2015.06.039
Hussain A Jiang S Varghese D Appukkuttan S Kebede N Gnanasakthy K Macahilig C Waldeck R Corman S Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States BMC Cancer 2022 22 304 10.1186/s12885-022-09364-z 35317768
Hussain A, Jiang S, Varghese D, Appukkuttan S, Kebede N, Gnanasakthy K, Macahilig C, Waldeck R, Corman S (2022) Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States. BMC Cancer 22:304. 10.1186/s12885-022-09364-z35317768 10.1186/s12885-022-09364-z
Katsuta M Nobeyama Y Hirafuku K Tashiro K Kimura T Asahina A Characteristics of mild and severe apalutamide-related cutaneous adverse events in patients with prostate cancer: a review of the literature J Dermatol 2024 51 110 114 10.1111/1346-8138.16972 37732499
Katsuta M, Nobeyama Y, Hirafuku K, Tashiro K, Kimura T, Asahina A (2024) Characteristics of mild and severe apalutamide-related cutaneous adverse events in patients with prostate cancer: a review of the literature. J Dermatol 51:110–114. 10.1111/1346-8138.1697237732499 10.1111/1346-8138.16972
Rönningås U Holm M Doveson S Fransson P Beckman L Wennman-Larsen A Signs and symptoms in relation to progression, experiences of an uncertain illness situation in men with metastatic castration-resistant prostate cancer-A qualitative study Eur J Cancer Care 2022 31 e13592 10.1111/ecc.13592
Rönningås U, Holm M, Doveson S, Fransson P, Beckman L, Wennman-Larsen A (2022) Signs and symptoms in relation to progression, experiences of an uncertain illness situation in men with metastatic castration-resistant prostate cancer-A qualitative study. Eur J Cancer Care 31:e13592. 10.1111/ecc.1359210.1111/ecc.13592
Saad F Small EJ Feng FY Graff JN Olmos D Hadaschik BA Oudard S Londhe A Bhaumik A Lopez-Gitlitz A Thomas S Mundle SD Chowdhury S Smith MR Deep prostate-specific Antigen response following addition of apalutamide to Ongoing Androgen Deprivation Therapy and Long-Term Clinical Benefit in SPARTAN Eur Urol 2022 81 184 192 10.1016/j.eururo.2021.11.020 34916086
Saad F, Small EJ, Feng FY, Graff JN, Olmos D, Hadaschik BA, Oudard S, Londhe A, Bhaumik A, Lopez-Gitlitz A, Thomas S, Mundle SD, Chowdhury S, Smith MR (2022) Deep prostate-specific Antigen response following addition of apalutamide to Ongoing Androgen Deprivation Therapy and Long-Term Clinical Benefit in SPARTAN. Eur Urol 81:184–192. 10.1016/j.eururo.2021.11.02034916086 10.1016/j.eururo.2021.11.020
Sánchez JC Picola N Rodriguez-Vida A Costa M Castañeda DM Márquez MP Rodriguez JM Gaya JM Bravo A Buisan O Servian P Suarez JF Felip MM Caparrós MJR Asensio AA Vilaseca A Apalutamide for prostate cancer: Multicentre and multidisciplinary real-world study of 227 patients Cancer Med 2023 12 21969 21977 10.1002/cam4.6769 38063364
Sánchez JC, Picola N, Rodriguez-Vida A, Costa M, Castañeda DM, Márquez MP, Rodriguez JM, Gaya JM, Bravo A, Buisan O, Servian P, Suarez JF, Felip MM, Caparrós MJR, Asensio AA, Vilaseca A (2023) Apalutamide for prostate cancer: Multicentre and multidisciplinary real-world study of 227 patients. Cancer Med 12:21969–21977. 10.1002/cam4.676938063364 10.1002/cam4.6769
Schad F Thronicke A Real-world evidence-current developments and perspectives Int J Environ Res Public Health 2022 19 10159 10.3390/ijerph191610159 36011793
Schad F, Thronicke A (2022) Real-world evidence-current developments and perspectives. Int J Environ Res Public Health 19:10159. 10.3390/ijerph19161015936011793 10.3390/ijerph191610159
Scher HI Solo K Valant J Todd MB Mehra M Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model PLoS ONE 2015 10 e0139440 e0139440 10.1371/journal.pone.0139440 26460686
Scher HI, Solo K, Valant J, Todd MB, Mehra M (2015) Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS ONE 10:e0139440–e0139440. 10.1371/journal.pone.013944026460686 10.1371/journal.pone.0139440
Smith MR Kabbinavar F Saad F Hussain A Gittelman MC Bilhartz DL Wynne C Murray R Zinner NR Schulman C Linnartz R Zheng M Goessl C Hei YJ Small EJ Cook R Higano CS Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer J Clin Oncol 2005 23 2918 2925 10.1200/JCO.2005.01.529 15860850
Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, Wynne C, Murray R, Zinner NR, Schulman C, Linnartz R, Zheng M, Goessl C, Hei YJ, Small EJ, Cook R, Higano CS (2005) Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 23:2918–2925. 10.1200/JCO.2005.01.52915860850 10.1200/JCO.2005.01.529
Smith MR Cook R Lee KA Nelson JB Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer Cancer 2011 117 2077 2085 10.1002/cncr.25762 21523719
Smith MR, Cook R, Lee KA, Nelson JB (2011) Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer 117:2077–2085. 10.1002/cncr.2576221523719 10.1002/cncr.25762
Smith MR Saad F Oudard S Shore N Fizazi K Sieber P Tombal B Damiao R Marx G Miller K Van Veldhuizen P Morote J Ye Z Dansey R Goessl C Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time J Clin Oncol 2013 31 3800 3806 10.1200/JCO.2012.44.6716 24043751
Smith MR, Saad F, Oudard S, Shore N, Fizazi K, Sieber P, Tombal B, Damiao R, Marx G, Miller K, Van Veldhuizen P, Morote J, Ye Z, Dansey R, Goessl C (2013) Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol 31:3800–3806. 10.1200/JCO.2012.44.671624043751 10.1200/JCO.2012.44.6716
Smith MR Saad F Chowdhury S Oudard S Hadaschik BA Graff JN Olmos D Mainwaring PN Lee JY Uemura H Lopez-Gitlitz A Trudel GC Espina BM Shu Y Park YC Rackoff WR Yu MK Small EJ SPARTAN Investigators Apalutamide Treatment and Metastasis-free survival in prostate Cancer N Engl J Med 2018 378 1408 1418 10.1056/NEJMoa1715546 29420164
Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ, SPARTAN Investigators (2018) Apalutamide Treatment and Metastasis-free survival in prostate Cancer. N Engl J Med 378:1408–1418. 10.1056/NEJMoa171554629420164 10.1056/NEJMoa1715546
Smith MR Saad F Chowdhury S Oudard S Hadaschik BA Graff JN Olmos D Mainwaring PN Lee JY Uemura H De Porre P Smith AA Brookman-May SD Li S Zhang K Rooney B Lopez-Gitlitz A Small EJ Apalutamide and overall survival in prostate Cancer Eur Urol 2021 79 150 158 10.1016/j.eururo.2020.08.011 32907777
Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ (2021) Apalutamide and overall survival in prostate Cancer. Eur Urol 79:150–158. 10.1016/j.eururo.2020.08.01132907777 10.1016/j.eururo.2020.08.011
