A post hoc exploratory analysis of the TITAN study evaluated prostate specific antigen (PSA) kinetics, including the speed, depth, and duration of PSA decline in patients with metastatic castration-sensitive prostate cancer (mCSPC) who were treated with apalutamide plus continuous androgen deprivation therapy (ADT) or placebo plus ADT. The association between achievement of deep PSA decline with clinical outcomes was also assessed.
Results show that addition of apalutamide to ADT results in a deep, rapid, and durable PSA decline in the majority of patients. This robust PSA decline seen with apalutamide plus ADT is associated with improved outcomes in overall survival (OS), radiographic progression-free survival (rPFS), time to PSA progression, and castration resistance in patients with mCSPC. Results confirm the prognostic impact of PSA decline and highlight the prognostic importance of PSA measurement in mCSPC according to Dr. Simon Chowdhury of the Department of Urological Cancer, Guy’s, King’s, and St Thomas’ Hospitals in London, UK and colleagues who published the findings on 26 February 2023 in the Annals of Oncology.
The authors wrote in the background that treatment objectives for patients with mCSPC are to delay disease progression to castration resistance and improve OS. Recent studies have demonstrated that the addition of other treatments/agents to ADT significantly improves outcomes in patients with mCSPC.
TITAN, a phase III, randomised, placebo-controlled study, demonstrated improved rPFS at 22.7 month follow-up, OS at 22.7 month and long-term 44.0 month follow-ups with an oral androgen signalling inhibitor, apalutamide added to ADT in a patient population with mCSPC versus placebo plus ADT. Additionally, PSA progression and castration resistance were delayed at long-term follow-up.
The ability to accurately prognosticate outcomes of treatment for mCSPC may help inform decisions for treatment selection, both intensification and de-escalation, and clinical management, especially frequency of visits and testing. In this post hoc exploratory analysis, the investigators evaluated PSA kinetics and the association between PSA decline and outcomes in patients with mCSPC from the TITAN study.
Patients received apalutamide (240 mg/day) plus ADT or placebo plus ADT and were randomised 1:1. In total, 1052 patients were enrolled, 525 in apalutamide plus ADT arm and 527 to placebo plus ADT arm. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of patients treated with apalutamide plus ADT versus 55%, 29%, and 32% in placebo plus ADT arm.
By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% in apalutamide plus ADT arm and in 13% and 18% in placebo plus ADT arm. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.25-0.48), rPFS (HR 0.44; CI 0.30-0.65), time to PSA progression (HR 0.31; CI 0.22-0.44), and time to castration resistance (HR 0.38; CI 0.27-0.52) compared with no decline (p < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of treatment with apalutamide.
The authors commented that their analysis used well-established landmark analysis methodology and is the first to assess the robustness of PSA decline with one of the androgen signalling inhibitors in mCSPC using data from the large prospective phase III clinical study with clinical practice implications. Future assessments of differences or similarities in PSA decline following apalutamide and the other androgen signalling inhibitors are intriguing.
Although the merit of PSA as a biomarker for response to treatment in patients with castration resistant prostate cancer has been challenged with a call for novel prostate cancer biomarkers, this post hoc analysis of TITAN demonstrates the value of PSA in making informed patient management and counselling decisions, such as the close monitoring for disease progression of patients with mCSPC who have a less robust PSA decline, and for clinical studies design.
Reference
S. Chowdhury, A. Bjartell, N. Agarwal, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Annals of Oncology; Published online 26 February 2023. DOI: https://doi.org/10.1016/j.annonc.2023.02.009