Prostrate CancerCorrelation of Prostate-specific Antigen Kinetics with Overall Survival and Radiological Progression-free Survival in Metastatic Castration-sensitive Prostate Cancer Treated with Abiraterone Acetate plus Prednisone or Placebos Added to Androgen Deprivation Therapy: Post Hoc Analysis of Phase 3 LATITUDE Study
Introduction
In developed countries, prostate cancer is the second most common cause of cancer deaths among men [1], although only a minority of men have metastatic castration-sensitive prostate cancer (mCSPC) at diagnosis [2]. However, the incidence of patients with metastatic disease at initial diagnosis is still significantly high in developing countries [3], [4]. Most prostate cancers will respond to androgen deprivation therapy (ADT) initially, but become resistant to ADT with a median time of approximately 1 yr [5], [6], [7]. The randomized, double-blind, active-controlled LATITUDE study compared efficacy and safety of abiraterone acetate plus low-dose prednisone (AAP) + ADT, with placebo for abiraterone acetate and prednisone (PBO) + ADT in men with high-risk mCSPC, demonstrating significantly longer overall survival (OS) and radiographic progression-free survival (rPFS) among patients receiving AAP + ADT, and established a new standard of care.
Prostate-specific antigen (PSA) decline and progression are well-established predictors of oncological outcomes in men treated with primary ADT and chemotherapy [8], [9], [10], [11], [12], [13], [14], [15], [16]. A threshold of PSA ≥ 0.2 ng/ml has been used as a predictor of progressive disease based on outcomes in various patient populations receiving ADT or radiotherapy [17]. Among patients with metastatic or high-risk localized prostate cancer, PSA ≥ 0.2 ng/ml at baseline and a shorter time to PSA nadir (TPN) are predictive of inferior OS [18], [19], [20]. With the availability of newer hormonal therapies, such as AAP, enzalutamide, darolutamide, or apalutamide, there is a need to identify potential predictors of progression that can serve as intermediate endpoints for survival in clinical trials and guide treatment in clinical practice.
A post hoc analysis of data from two large AAP studies [21], [22] in men with metastatic castration-resistant prostate cancer (mCRPC) assessed the correlation between AAP treatment effect and PSA kinetics. In this setting, PSA nadir, PSA response rate, and time to PSA progression (TPP) were highly correlated with the long-term outcome of OS [23]. However, there is a scarcity of published data on the association between PSA kinetics and oncological outcomes in patients with mCSPC who were treated with new hormonal agents.
This post hoc analysis assessed the correlation of PSA kinetics with rPFS and OS in patients in the LATITUDE study to identify potential markers for further evaluation.
Section snippets
Study design and data collection
LATITUDE was a double-blind, placebo-controlled phase 3 trial comparing the efficacy and safety of abiraterone acetate 1000 mg plus prednisone 5 mg administered orally once a day in addition to ADT versus dual PBO + ADT in men with mCSPC [24]. Patients were required to have at least two of the following risk factors associated with poor prognosis: Gleason score ≥8 (from a range of scores of 2–10, with higher scores indicating more aggressive disease), three or more bone lesions, and presence of
Patients
In the LATITUDE study [24], [26], 1199 men with mCSPC were randomized to receive AAP + ADT (n = 597) or PBO + ADT (n = 602). As described in previously published data, baseline demographic and disease characteristics were similar in the two treatment groups. The median PSA level at baseline was 25.43 ng/ml in the AAP + ADT group and 23.05 ng/ml in the PBO + ADT group.
Time to PSA progression
AAP + ADT significantly delayed the median TPP versus PBO + ADT (33.2 vs 7.4 mo; HR: 0.3, p < 0.001; Fig. 1A). Moreover, TPP
Discussion
This post hoc analysis of data from patients with high-risk mCSPC enrolled in LATITUDE investigated PSA dynamics as predictors of long-term treatment outcomes. In LATITUDE, patients receiving AAP + ADT had significantly longer rPFS and OS than patients receiving PBO + ADT. In the current analysis, both depth and durability of PSA responses measured by PSA50 response, PSA90 response, and decline to PSA levels ≤0.1 ng/ml in ≤6 mo were favorably correlated with long-term study outcomes of rPFS and
Conclusions
Addition of AAP to ADT for treatment of mCSPC significantly increased the magnitude and depth of PSA response, which strongly correlated with long-term outcomes of rPFS and improved OS. Therefore, PSA response evaluation in AAP + ADT treatment of mCSPC may have immediate and long-term clinical relevance.
Author contributions: Nobuaki Matsubara had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept
References (28)
- et al.
Incidence and mortality of prostate cancer and their relationship with the Human Development Index worldwide
Prostate Int
(2016) - et al.
Survival with newly diagnosed metastatic prostate cancer in the "docetaxel era": data from 917 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019)
Eur Urol
(2015) - et al.
Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial
Lancet Oncol
(2013) - et al.
Multiple rechallenges for castration-resistant prostate cancer patients responding to first-line docetaxel: assessment of clinical outcomes and predictive factors
Urology
(2012) - et al.
Time to prostate-specific antigen nadir and the risk of death from prostate cancer following radiation and androgen deprivation therapy
Urology
(2019) - et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol
(2012) - et al.
Increasing incidence of metastatic prostate cancer in the United States (2004–2013)
Prostate Cancer Prostatic Dis
(2016) - et al.
Risk assessment among prostate cancer patients receiving primary androgen deprivation therapy
J Clin Oncol
(2009) Prostate cancer in Asian men
Nat Rev Urol
(2014)- et al.
Chemohormonal therapy in metastatic hormone-sensitive prostate cancer
N Engl J Med
(2015)
Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group
J Clin Oncol
Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16
J Natl Cancer Inst
Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer
J Clin Oncol
A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis
Clin Cancer Res
Cited by (51)
Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study
2023, Urologic Oncology: Seminars and Original InvestigationsAttainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide
2023, Urologic Oncology: Seminars and Original InvestigationsDefining Patient Benefits from High-intensity Intermittent Therapy for Hormone-sensitive Prostate Cancer
2023, European Urology FocusEmergence of triplet therapy for metastatic castration-sensitive prostate cancer: An updated systematic review and network meta-analysis
2023, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :The latter 2 trials included triplet therapy with darolutamide [11] or abiraterone [12] in combination with ADT and docetaxel. Dual therapy agent included abiraterone (LATITUDE [13–20], STAMPEDE [21–25]), apalutamide [26–31], docetaxel (CHAARTED [32–40], GETUG-AFU15 [34,41], STAMPEDE [42]) and enzalutamide(ARCHES4-10), ENZAMET [40,43,44]) in combination with ADT. There was updated data available for included trials since our last analysis [25,29,45].