Elsevier

European Urology

Volume 77, Issue 4, April 2020, Pages 494-500
European Urology

Prostrate Cancer
Correlation 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

https://doi.org/10.1016/j.eururo.2019.11.021Get rights and content

Abstract

Background

LATITUDE, a randomized, double-blind trial, compared abiraterone acetate and prednisone (AAP) + androgen deprivation therapy (ADT) versus placebo (PBO) + ADT in high-risk metastatic castration-sensitive prostate cancer (mCSPC).

Objective

To assess the correlation of prostate-specific antigen (PSA) kinetics with overall survival (OS) and radiological progression-free survival (rPFS).

Design, setting, and participants

A post hoc analysis of data from 597 men receiving AAP + ADT and 602 receiving PBO + ADT.

Outcome measurements and statistical analysis

The associations of PSA-related outcomes (rates of confirmed 50% [PSA50] and 90% [PSA90] decline from baseline PSA [Prostate Cancer Working Group 2 criteria], rates of PSA < 0.2 ng/ml, median nadir PSA, time to PSA nadir [TPN], and time to PSA progression [TPP] with long-term outcomes [OS and rPFS]) were evaluated. Hazard ratios (HRs) were estimated using Cox proportional hazard model. Correlations of TPP with coprimary endpoints rPFS and OS were evaluated using Kendall’s tau (KT).

Results and limitations

AAP + ADT significantly delayed median TPP versus PBO + ADT (33.2 vs 7.4 mo; HR: 0.3, p <  0.001). TPP correlated with rPFS (KT = 0.921) and OS (KT = 0.666). In the AAP + ADT group, 91% had PSA50 and 79% had PSA90 responses (relative risk [RR]: 1.36 and 2.30, respectively; p <  0.001 for both comparisons vs PBO + ADT). Compared with nonresponders, PSA50 and PSA90 responders had reduced risk of death (RR: 0.44 and 0.12, respectively). At 6 mo, 40% receiving AAP + ADT and 6.5% receiving PBO + ADT achieved PSA ≤0.1 ng/ml, which was significantly associated with longer rPFS and OS. Median nadir PSA was 0.09 ng/ml with AAP + ADT versus 2.36 ng/ml with PBO + ADT. Median TPN (AAP + ADT, 6.4 mo; PBO + ADT, 3.8 mo) positively correlated with rPFS and OS.

Conclusions

Superior PSA response dynamics with AAP + ADT versus ADT + PBO strongly correlated with long-term outcomes of rPFS and OS in high-risk mCSPC.

Patient summary

We found that low prostate-specific antigen levels (≤0.1 ng/ml) after 6 mo may indicate a good long-term response to treatment. Our results need confirmation.

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)

  • G.J. Bubley et al.

    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

    (1999)
  • D.P. Petrylak et al.

    Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16

    J Natl Cancer Inst

    (2006)
  • A.J. Armstrong et al.

    Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer

    J Clin Oncol

    (2007)
  • A.J. Armstrong et al.

    A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis

    Clin Cancer Res

    (2007)
  • Cited by (51)

    • Emergence of triplet therapy for metastatic castration-sensitive prostate cancer: An updated systematic review and network meta-analysis

      2023, Urologic Oncology: Seminars and Original Investigations
      Citation 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].

    View all citing articles on Scopus
    View full text