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Year : 2020  |  Volume : 36  |  Issue : 2  |  Page : 144-145
 

TITAN trial; shifting focus from hormone-refractory to hormone-sensitive prostate cancer


Department of Urology, AIIMS, Bhubaneswar, Odisha, India

Date of Submission03-Nov-2019
Date of Acceptance18-Jan-2020
Date of Web Publication07-Apr-2020

Correspondence Address:
Gautam Kumar
Department of Urology, AIIMS, Bhubaneswar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/iju.IJU_315_19

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How to cite this article:
Kumar G. TITAN trial; shifting focus from hormone-refractory to hormone-sensitive prostate cancer. Indian J Urol 2020;36:144-5

How to cite this URL:
Kumar G. TITAN trial; shifting focus from hormone-refractory to hormone-sensitive prostate cancer. Indian J Urol [serial online] 2020 [cited 2020 Dec 4];36:144-5. Available from: https://www.indianjurol.com/text.asp?2020/36/2/144/281955



   Summary Top


The recently published TITAN trial evaluated the role of adding apalutamide in metastatic castration-sensitive prostate cancer (mCSPC). Currently, androgen deprivation therapy (ADT) + docetaxel and ADT + abiraterone are the standard treatments of mCSPC. Apalutamide (ARN509) is an irreversible nonsteroidal androgen receptor antagonist. The TITAN trial is a phase 3, randomized, double-blind, placebo-controlled trial on apalutamide + ADT versus ADT alone in mCSPC. Results of the trialhave been published in the New England Journal of Medicine in July 2019.[1] It included CSPC patients with distant metastatic disease measured by ≥1 lesion on bone scan, with or without visceral/lymph node involvement and ECOG performance status of 0–1. A total of 1052 patients were enrolled in two Groups: Group 1 (apalutamide 240 mg plus ADT) – n = 525 and Group 2 (placebo + ADT) – n = 527. The overall survival (OS) at 24 months was 82.4% in the Group 1 and 73.5% in the Group 2 (33% risk reduction of death). At 2 years, the radiographic progression-free survival was 68% in Group 1 and 48% in Group 2 (52% risk reduction of radiographic progression or death). OS benefit was also consistent through all the subgroups. It also prolonged time to cytotoxic chemotherapy (61% risk reduction) and second PFS (32% risk reduction). Most common side effect was rash (27% in Group 1 and 8.5% in Group 2), and the most common adverse event of Grade 3 or higher was also rash of any type (6.3%). Hypothyroidism was seen in 6.5% of the patients in the apalutamide group.


   Commentary Top


The focus of recent advances in carcinoma prostate has now shifted from the management of castrate-resistant to castrate-sensitive patients. Various trials and the median OS for mCSPC are summarized in [Table 1].
Table 1: Summary of trials on metastatic castrate sensitive prostate cancer

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In a meta-analysis that included CHAARTED, STAMPEDE arm C, and GETUG-AFU 15 trial data, ADT + docetaxel was confirmed to significantly improve the median OS (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.68–0.87) and the median failure-free survival (HR 0.64; 95% CI 0.58–0.70) compared with ADT alone. CHAARTED/STAMPEDE (arm C/E), GETUG-AFU15, and subsequent meta-analysis established ADT + docetaxel as a standard of care (SOC) for high-volume mCSPC with good performance status and LATITUDE/STAMPEDE arm G, established ADT + abiraterone acetate and prednisone as a SOC for mCSPC, regardless of the disease volume status and performance status. Therefore, ADT + docetaxel should be preferred for men with good performance status, who have high-volume disease, desire shorter total treatment time, or have concerns of prescription drug costs, while ADT + abiraterone should be considered for men regardless of disease volume, who desire to avoid possible chemotherapy toxicity, or who want to minimize facility visits for docetaxel administration. ADT + apalutamide is a new addition with similar benefit and can be added to men where abiraterone is not tolerated (due to mineralocorticoid excess) or is discontinued due to toxicity (hepatotoxicity).

Apalutamide is preferred over enzalutamide because the ARCHES trial showed that for men with liver metastasis, enzalutamide has no discernible benefit.[5] Again, during the preclinical development in animal model, apalutamide as compared to enzalutamide showed a steady-state plasma concentration 2–4-fold lower for the equivalent doses, whereas inter-tumoral level was roughly equivalent, with a greater antitumor activity at a lower dose and higher tumor/plasma ratio.[6] Brain (central nervous system) level of apalutamide were 4-fold lower than those observed with enzalutamide, indicating a lower risk of seizure activity.[6]

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.



 
   References Top

1.
Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for metastatic, castration-sensitive prostate cancer (TITAN). N Engl J Med 2019;381:13-24.  Back to cited text no. 1
    
2.
James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-77.  Back to cited text no. 2
    
3.
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): Final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol 2019;20:686-700.  Back to cited text no. 3
    
4.
Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37:2974-86.  Back to cited text no. 4
    
5.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33.  Back to cited text no. 5
    
6.
Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. ARN-509: A novel antiandrogen for prostate cancer treatment. Cancer Res 2012;72:1494-503.  Back to cited text no. 6
    



 
 
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