SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022, and 34,500 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.
The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patient’s with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.
ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. Apalutamide is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer and non-metastatic Castration Resistant Prostate Cancer. ZYTIGA® (Abiraterone) is a selective, irreversible inhibitor of CYP 17A1 enzyme and decreases androgen biosynthesis in the testes, adrenal glands, and prostate-tumor tissue. Both Apalutamide and Abiraterone plus prednisone have been shown to prolong Overall Survival in the metastatic prostate cancer.
The purpose of this study was to evaluate if intensification of Androgen Deprivation Therapy (ADT) prolongs biochemical Progression Free Survival (PFS), in patients with biochemically relapsed prostate cancer. PRESTO is a randomized, open-label Phase III trial, in which 504 prostate cancer patients who had radical prostatectomy were included. Study patients had biochemical recurrence (PSA more than 0.05 ng/mL), a PSA doubling time of 9 months or less, and without distant metastases on conventional imaging (CT and Bone scan). Patients were randomized 1:1:1 to receive a finite 52-week treatment course with ADT alone (N=167), ADT plus Apalutamide (N=168), or ADT plus Apalutamide plus Abiraterone/Prednisone (N=169). Patients were stratified by PSA doubling time (less than 3 months versus 3-9 months) and patients were followed up following treatment completion with mostly lab assessment until PSA progression, at which point, treatment was per investigator discretion. Patient and disease characteristics at baseline were well balanced among the 3 study groups. The median age was 67 years and 84% of patients were white. The median PSA at baseline was 1.77 ng/mL. The PSA doubling time was less than 3 months for 26% of patients and between 3 and 9 months for 74% of patients. The median time between radical prostatectomy and baseline was 4.4 years. Overall, 85% of patients had prior radiation and 42% of patients had prior ADT. The Primary endpoint of the study was to compare biochemical Progression Free Survival (defined as increase in serum PSA of more than 0.2 ng/mL following treatment) in each experimental group with ADT alone. Secondary endpoints included safety, patient-reported Quality of Life (QOL), time to testosterone recovery (more than 50 ng/dL following treatment completion), Metastasis-Free Survival, and time to castration resistance.
The first planned interim analysis at a median follow-up of 21.5 months showed that both study groups significantly prolonged biochemical PFS compared to the control group. The median biochemical (PSA) PFS was 24.9 months with Apalutamide plus ADT versus 20.3 months with ADT alone (HR=0.52; P=0.00047). The median biochemical PFS was 26.0 months with ADT plus Apalutamide plus Abiraterone/Prednisone versus 20.0 months with ADT alone (HR=0.48; P=0.00008). A preplanned subgroup analysis based on stratification by PSA doubling time showed a consistent benefit in both study groups, compared to the control group, regardless of the length of PSA doubling time. The median time to testosterone recovery following treatment completion was 3.9 months with ADT alone, 3.8 months with Apalutamide plus ADT and 4.7 months with ADT plus Apalutamide plus Abiraterone/Prednisone. There was an increase in the incidence of adverse events with the addition of Abiraterone.
It was concluded that intensifying Androgen Receptor blockade with Apalutamide plus Androgen Deprivation Therapy prolongs biochemical PFS with a manageable safety profile and without impacting time to testosterone recovery, following a finite duration of treatment. The authors added that intensification of Androgen Receptor blockade should be considered in high-risk biochemically relapsed prostate cancer.
LBA63 – PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19). Aggarwal R, Heller G, Hillman D, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089
