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.

The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. 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 apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. 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; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% 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 apalutamide treatment. Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Chowdhury S ，Bjartell A ，Agarwal N ，Chung BH ，Given RW ，Pereira de Santana Gomes AJ ，Merseburger AS ，Özgüroğlu M ，Juárez Soto Á ，Uemura H ，Ye D ，Brookman-May SD ，Londhe A ，Bhaumik A ，Mundle SD ，Larsen JS ，McCarthy SA ，Chi KN ... -  《-》

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN.

Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. Apalutamide 240 mg/d. The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p < 0.001 for all). Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.

Saad F ，Small EJ ，Feng FY ，Graff JN ，Olmos D ，Hadaschik BA ，Oudard S ，Londhe A ，Bhaumik A ，Lopez-Gitlitz A ，Thomas S ，Mundle SD ，Chowdhury S ，Smith MR ... -  《-》

Prostate-specific antigen (PSA) decline with apalutamide therapy is associated with longer survival and improved outcomes in individuals with metastatic prostate cancer: a plain language summary of the TITAN study.

Chowdhury S ，Bjartell A ，Agarwal N ，Chung BH ，Given RW ，Pereira de Santana Gomes AJ ，Merseburger AS ，Özgüroğlu M ，Soto ÁJ ，Uemura H ，Ye DW ，Brookman-May SD ，Londhe A ，Bhaumik A ，Mundle SD ，Larsen JS ，McCarthy SA ，Chi KN ... -  《-》

Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.

To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.

Merseburger AS ，Agarwal N ，Bjartell A ，Uemura H ，Soto AJ ，Bhaumik A ，Böhm J ，Tran N ，Krochmann N ，Nematian-Samani M ，Mundle SD ，Brookman-May SD ，Lopez-Gitlitz A ，McCarthy SA ，Chi K ，Chowdhury S ... -  《-》

Post Hoc Analysis of Rapid and Deep Prostate-specific Antigen Decline and Patient-reported Health-related Quality of Life in SPARTAN and TITAN Patients with Advanced Prostate Cancer.

Small EJ ，Chi KN ，Chowdhury S ，Bevans KB ，Bhaumik A ，Saad F ，Chung BH ，Karsh LI ，Oudard S ，De Porre P ，Brookman-May SD ，McCarthy SA ，Mundle SD ，Uemura H ，Smith MR ，Agarwal N ... -  《European Urology Oncology》