Early Prostate-Specific Antigen Response by 6 Months Is Predictive of Treatment Effect in Metastatic Hormone Sensitive Prostate Cancer: An Exploratory Analysis of TITAN Trial.

PURPOSE: Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients. MATERIALS AND METHODS: Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS. RESULTS: Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS (P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months (P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively. CONCLUSIONS: Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

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

OBJECTIVE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.

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.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from an additional (or post hoc) analysis of the TITAN study. The TITAN study looked at whether the prostate cancer treatment apalutamide could be used to treat individuals with metastatic castration-sensitive prostate cancer (or mCSPC). A total of 1052 participants with mCSPC were included in the TITAN study. Treatment with apalutamide was compared with treatment with placebo. All participants received androgen deprivation therapy (or ADT), which is a type of hormone therapy that has been part of the main treatment for mCSPC for many years. The results showed that apalutamide plus ADT increased the length of time that participants remained alive compared with placebo plus ADT. Apalutamide plus ADT also controlled the growth of the cancer for a longer length of time compared with placebo plus ADT. Additionally, participants who received apalutamide plus ADT experienced a greater reduction in the blood levels of prostate-specific antigen (or PSA), called a deep PSA decline, compared with those who received placebo plus ADT. An additional (or post hoc) analysis was carried out to understand whether a decrease in blood PSA levels, in response to treatment, was associated with improved outcomes, including longer survival time. WHAT WERE THE RESULTS OF THE ADDITIONAL ANALYSIS?: In participants who received apalutamide plus ADT, a deep PSA decline in response to treatment was associated with longer survival time and improved outcomes. WHAT DO THESE RESULTS MEAN FOR INDIVIDUALS WITH MCSPC?: These results demonstrate that individuals with mCSPC can benefit from treatment with apalutamide plus ADT. The association seen between deep PSA decline and the longer survival time and improved outcomes highlights how PSA measurements can be used to help monitor cancer disease evolution in response to treatment. Monitoring PSA levels will assist doctors and other healthcare professionals to understand how effectively a treatment is working for a patient and to tailor their treatment approach to improve PSA decline.

A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia.

Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.