Ma, Ting Martin

PURPOSE The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer–specific mortality. RESULTS Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points ( P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer–specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

277 Background: The prognostic importance of local failure (LF) after definitive radiotherapy (RT) in patients with NCCN intermediate- (IRPCa) and high-risk prostate cancer (HRPCa) remains unclear, particularly given the likelihood that occult distant metastases (DMs) at presentation may be the true driver of natural history. Here, we leverage individual patient data (IPD) from 18 randomized control trials (RCTs) to evaluate the prognostic impact of LF and the kinetics of DM after RT. Methods: IPD for 18 RCTs were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, comprising a total of 12533 patients (6288 HRPCa & 6245 IRPCa). Multivariable Cox proportional hazards (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), DM-free survival (DMFS) & LF as a time-dependent covariate, adjusted for clinicodemographic parameters. Markov PH models, defined via transitions between 4 states, were developed to evaluate the aforementioned relationship. Proportional hazards assumption was imposed and examined for both models. Time is from randomization. Results: Median follow-up was 9.1 years. There were 795 (13%) LF & 1288 (21%) DM events for patients with HRPCa; these numbers were 449 (7%) & 451 (7%) for IRPCa. For HRPCa & IRPCa, 81% and 81% of DMs developed from a clinically relapse-free state (cRFS), with a median time of 46 and 60 months, respectively (p < 0.0001). 39% & 13% of DM events occurred within 2 years after RT for HRPCa & IRPCa, respectively. At later time points, DM events were more likely to emerge after an LF event for both HRPCa (9% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.001) and IRPCa (10% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.008). LF was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75-2.33) & DMFS (HR 1.94, 95% CI 1.75–2.15) (p < 0.01 for all) in patients with HRPCa. LF was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not OS in patients with IRPCa. Patients who had not transitioned to the LF state had a significantly lower HR of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.32, 95% CI 0.21–0.50, p < 0.001). Conclusions: LF is an independent prognosticator of OS, PCSS & DMFS in HRPCa and of DMFS in IRPCa. The predominant mode of DM development is from the cRFS state, underscoring the importance of accurate upfront staging & systemic therapy. However, particularly at late time points, an increasing proportion of DM events originated after diagnosis of a LF, constituting a “second wave” of DM events. This suggests that optimizing local control is also important, though the majority of DM events appear prior to a clinically-detected LF.