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Year : 2020  |  Volume : 36  |  Issue : 1  |  Page : 71-72
 

LATITUDE: A landmark trial for high-risk metastatic castration-sensitive prostate cancer: Final overall survival analysis


Department of Urology, AIIMS, Bhubaneshwar, Odisha, India

Date of Submission01-Sep-2019
Date of Acceptance02-Nov-2019
Date of Web Publication2-Jan-2020

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


DOI: 10.4103/iju.IJU_258_19

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How to cite this article:
Kumar G. LATITUDE: A landmark trial for high-risk metastatic castration-sensitive prostate cancer: Final overall survival analysis. Indian J Urol 2020;36:71-2

How to cite this URL:
Kumar G. LATITUDE: A landmark trial for high-risk metastatic castration-sensitive prostate cancer: Final overall survival analysis. Indian J Urol [serial online] 2020 [cited 2020 Feb 25];36:71-2. Available from: http://www.indianjurol.com/text.asp?2020/36/1/71/274695



   Summary Top


LATITUDE was a multicenter, randomized, double-blind, phase 3 trial on high-risk metastatic castration-sensitive prostate cancer (mCSPC).[1] The inclusion criteria were men who fulfilled at least two of the three high-risk prognostic factors (GS ≥8, ≥3 lesions on bone scan, and visceral metastases, excluding lymph node metastasis). It included men with histologically/cytologically confirmed adenocarcinoma prostate, with distant metastatic disease (documented by positive bone scan or metastatic lesions on computed tomography or magnetic resonance imaging) and ECOG performance status of 0–2. The exclusion criteria were men with neuroendocrine differentiation/small cell histology, brain metastasis, uncontrolled hypertension, or clinically significant cardiac, adrenal, or liver disease, or malignancy other than prostate or nonmelanoma skin cancer <5 years. Patients who had received previous chemotherapy, radiotherapy, or surgery for metastatic prostate were also excluded from the study.

A total of 1199 patients were enrolled in two groups: Group 1 (AA 250 mg, 4 tablet and prednisone 5 mg plus ADT) n = 597 and Group 2 (placebo plus ADT) n = 602. For ADT, luteinizing hormone-releasing hormone agonists were used unless the patient was surgically castrated. The first interim analysis showed a 38% risk reduction of death (RRoD) compared to Group 2 and the overall rate of survival (OS) at 3 years was 66% in Group 1 and 49% in the Group 2. The second interim analysis showed 36% RRoD in Group 1 versus Group 2. At the present final analysis, 46% (n = 275) in Group 1 and 57% (n = 343) in Group 2 had died, with a median follow-up of 51.8 months.[1] Seventy-two patients had crossed over from Group 2 to Group 1 and none from Group 1 to Group 2. Median OS was longer in Group 1 (53.3 vs. 36.5 months) (95% confidence interval [CI] 48·2 − not reached) than in Group 2 (95% CI 48·2 − not reached).

The secondary endpoints (SEP) such as pain progression (41% vs. 49%), skeletal-related events (22% vs. 25%), subsequent prostate cancer therapy (SPCT) (42% vs. 59%), and even PSA progression (33.3 vs. 7.4 months) were better in Group 1 than that of Group 2.

The overall incidence of adverse events (AEs) was 95% in Group 1 versus 93% in Group 2. Grade 3–4 AEs were seen in 68% in Group 1 versus 50% in Group 2, and the most common Grade 3–4 AEs were hypertension (21% in Group 1 vs. 10% in Group 2). Treatment-related serious AEs were seen in 5% in Group 1 versus 2% in Group 2 and the most common being hypokalemia (1% in Group 1 vs. 0% in Group 2). AEs leading to treatment discontinuation were reported in 16% in Group 1 versus 10% in Group 2 and dose reduction or interruption in 35% in Group 1 versus 18% in Group 2. Overall, AEs leading to death were seen in 6% in Group 1 versus 4% in Group 2.

The authors conclude that the LATITUDE trial provides Level 1 evidence regarding survival benefit of 16.8 months (53.3 vs. 36.5 months) in the early use of AAP with ADT over ADT alone in high-risk mCSCP with a long-term follow-up of 51.8 months. Pain progression was delayed by 30.8 months and more importantly PSA progression was delayed by 25.9 months, respectively, over ADT alone.


   Commentary Top


This landmark trial[1] confirmed that use of AAP with ADT in mCSPC with HRD showed a significant improvement in OS and SEP but not in men with ECOG >2 and GS ≤8. Decreased need for SPCT (42% vs. 59%) and improved secondary-PFS (53.3 vs. 30.1 months) shows that the addition of AA and prednisolone (AAP) early retained therapeutic advantage even after the end of treatment and this supports its early use.[1] SPCT was required in 57% of this trial and 32% in STAMPEDE trial (Arm C),[2] and these are the men which enter mCRPC status, reflecting the real future scenario of these men. The STAMPEDE (Arm G) trial has recruited larger number of patients (960 in AAP arm and 967 in ADT arm vs. 597 in AAP arm and 602 in ADT arm in the LATITUDE trial). Its enrollment has been completed, and it is estimated that the final analysis would be available by September 2024. The OS for AAP arm was not reached versus 53.3 months and for ADT arm was 48 months versus 34.3 months in the STAMPEDE (Arm G) and LATITUDE trials, respectively.

There was no significant survival advantage of AAP in low-risk and low-volume disease (LR–LVD) in the LATITUDE trial, unlike the STAMPEDE (Arm G) trial, which showed benefit and had 48% of patients with LR–LVD. However, a significant improvement in (rPFS) radiological progression free survival was found in both the trials.

A post-hoc analysis from STAMPEDE found that PFS, but not OS, might be longer with AAP than with docetaxel.[3] However, evidence is maturing in favor of docetaxel that its efficacy is impaired after the use of abiraterone or enzalutamide,[4] and therefore, docetaxel should be used before abiraterone. Docetaxel is also cheaper due to 6–9 cycles of therapy as compared to life-long use of abiraterone.

Whether men who were excluded (who had received previous chemotherapy, radiotherapy, or surgery for metastatic prostate) or who developed a high-risk metastatic relapse after local treatment of their primary prostate cancer could benefit from AAP are unknown and the best therapy for these men is also unknown.

While the previous two interim analysis of this trial gave evidence of improvement in OS and rPFS in men receiving AAP over ADT only, the final analysis reports the exact quantum of improvements in months. Data on SEP such as pain progression, skeletal-related events, SPCT, and PSA progression were also available from this final analysis.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

 
   References Top

1.
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. 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.
Feyerabend S, Saad F, Li T, Ito T, Diels J, Van Sanden S, et al. Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis. Eur J Cancer 2018;103:78-87.  Back to cited text no. 3
    
4.
Sharma AP, Mavuduru RS, Bora GS, Devana SK, Singh SK, Mandal AK. STAMPEDEing metastatic prostate cancer: CHAARTing the LATITUDEs. Indian J Urol 2018;34:180-4.  Back to cited text no. 4
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