PSA Decline With Apalutamide Yields Improved Survival in Prostate Cancer

Apalutamide (Erleada) plus androgen deprivation therapy (ADT) yielded more robust, deep, and rapid declines in prostate-specific antigen (PSA) levels than placebo plus ADT in patients with metastatic castration-sensitive prostate cancer (CSPC), and these declines were associated with improved survival outcomes, according to a recent post hoc analysis of the phase 3 TITAN trial (NCT02489318).

"Our analysis of PSA decline in TITAN shows that patients who rapidly achieved deep PSA decline following apalutamide treatment derived a long-term clinical benefit," according to the study authors.

From baseline, 90% of patients in the apalutamide group had a best confirmed PSA decline of 50% or greater at any time; 73% had a decline of 90% or greater, 68% had a decline to undetectable levels of 0.2 ng/mL or less, and 85% had a PSA decline of 90% or more or 0.2 ng/mL or greater. The corresponding figures in the placebo group were 55%, 29%, 32%, and 43%, respectively.

At 3 months, 59% of those treated with apalutamide had a best deep PSA decline of 90% or greater as compared with 13% of those in the placebo group; additionally, a decline to 0.2 ng/mL or less occurred in 51% vs 18%, respectively.

A deep PSA decline at 3 months with apalutamide was associated with longer overall survival (Hazard ratio [HR], 0.35; 95% CI, 0.25-0.48; P <.0001), radiographic progression-free survival (HR, 0.44; 95% CI, 0.30-0.65; P <.0001), time to PSA progression (HR, 0.31; 95% CI, 0.22-0.44; P <.0001), and time to castration resistance (HR 0.38; 95% CI, 0.27-0.52; P <.0001) vs no decline. Similar associations also occurred at the 6- and 12-month time points.

“To our knowledge, this is the first demonstration of the association of PSA decline with progression to castration-resistant prostate cancer (CRPC),” the investigators wrote. “Our analysis of PSA decline in TITAN shows that patients who rapidly achieved deep PSA decline following apalutamide treatment derived a long-term clinical benefit…. Our results highlight the prognostic importance of PSA measurement in metastatic CSPC.”

The post hoc analysis included 1052 patients from the randomized, double-blind, placebo-controlled, multinational phase 3 TITAN study. The trial included 525 patients in the apalutamide group and 527 in the placebo group. A median of 1.8 months elapsed between initiation of ADT and randomization in the study population. Overall, 81% of patients had de novo metastatic disease, and 14% had localized disease.

The treatment groups had similar baseline median serum levels of PSA, with a median of 5.97 ng/mL in the apalutamide group and 4.02 ng/mL in the placebo group. Median PSA nadirs were 0.02 ng/mL with apalutamide vs 0.75 ng/mL with placebo, and the median time to nadir was 5.6 months vs 4.6 months, respectively.

Patients in the TITAN trial received apalutamide or placebo at a dose of 240 mg per day as well as ADT. Measurements of serum PSA levels were taken at screening and on the first day of each treatment cycle until cycle 13, every other cycle until cycle 25, and every 4 cycles thereafter until the end of treatment.

In addition to the other associations, investigators found that the proportion of patients who achieved both 90% or greater PSA decline and PSA levels of 0.2 ng/mL or lower increased from 35% at 3 months to 47% at 6 months and 52% at 12 months with apalutamide. The corresponding proportions were 3% at 3 months, 5% at 6 months, and 7% at 12 months with placebo.

“Future assessments of differences or similarities in PSA decline following apalutamide and the other androgen signaling inhibitors are intriguing. Although the merit of PSA as a biomarker for response to treatment in patients with CRPC 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 metastatic CSPC who have a less robust PSA decline, and for clinical trial designs.” the investigators concluded

Reference

Chowdhury S, Bjartell A, Agarwal N, 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. Ann Oncol. 2023;34(5):477-485. doi:10.1016/j.annonc.2023.02.009