Association of Prostate Specific Antigen Kinetics after Testosterone Recovery with Subsequent Recurrence: Secondary Analysis of a Phase Ill Randomized Controlled Trial

The combination of short-term androgen deprivation therapy (ST-ADT) with prostate radiotherapy (RT) is a standard of care for patients with localized prostate cancer (LPCa). After cessation of ST-ADT, it takes about 8 to 10 months for the testosterone (T) to recover to supracastrate levels, which could drive changes in PSA kinetics. It largely remains unknown whether early changes in PSA kinetics after T recovery could predict for subsequent biochemical relapse.We performed a secondary analysis of a phase III randomized controlled trial in which patients with newly diagnosed LPCa with Gleason score £7, clinical stage T1b to T3a, and PSA <30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT (76 Gy in 38 fractions over 7.5 weeks) or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. Clinical assessment and laboratory investigations were repeated 1 month after completion of ADT, every 4 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after recovery of T to a supracastrate level (>50 ng/dL). Patients with ³3 PSA measurements after T recovery to supracastrate level were included in this analysis. Fine and Gray cumulative incidence of biochemical recurrence (BCR) was calculated in patients with PSADT at or above median versus below median. Deaths were considered as competing events. All endpoints were calculated from the time of T recovery to supracastrate level. Subdistribution hazard ratios (sHR) with 95% confidence intervals (CI) were estimated for association of PSADT with relative incidence of recurrence using competing risk regression after adjusting for tumor stage, pre-treatment PSA, Gleason score, treatment regimen, and age at randomization.Overall, 311 patients were eligible for this analysis. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years was 31.0% and 20.7% in patients with PSADT <8 months and ³8 months, respectively. Longer PSADT was associated with a significantly lower risk of cumulative incidence of BCR (sHR for PSADT as a continuous variable 0.43, 95% CI: 0.28-0.66; sHR for PSADT ³8 months 0.54, 95% CI: 0.30-0.99). After adjustment for time to recovery of T to supracastrate level in addition to the aforementioned variables, longer PSADT (³8 months) was associated with lower risk of cumulative incidence of BCR (sHR: 0.53, 95% CI: 0.27-1.01).These findings suggest that early PSA kinetics within 18 months of recovery of T to a supracastrate level predict for subsequent biochemical failure. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit greater personalization of management decisions.