In this study, we found that men with moderate or severe comorbidity did not have significantly higher estimates of PCSM or ACM following PSA failure, despite having a rapid as compared with a slow increase in their PSA level during the year prior to PSA failure. Conversely, men with no or minimal comorbidity had significantly higher estimates of both PCSM and ACM following PSA failure when their PSA rise leading to PSA failure was rapid as compared with slow. Therefore, the increase in ACM among men in otherwise good health can be explained by the marked increase in estimates of PCSM among men with a rapid as compared to a slow increase in PSA (Fig. 2). The clinical significance of these findings is 2-fold. First, given the recent RCT finding that intermittent AST was noninferior to continuous AST for men who experienced PSA failure following RT, one could justify the next RCT comparing the impact of intermittent AST as compared to surveillance in men with moderate or severe comorbidity with a prerandomization stratification for rapid versus a slow rise in PSA. It remains unclear whether any AST is beneficial in men with moderate to severe comorbidity, particularly those with a slow rise in their PSA, and therefore such a trial would be justified. Second, given the survival benefit observed in men undergoing either abiraterone or enzalutamide therapy for castration-resistant metastatic PC and the high death rate from PC in men with no or minimal comorbidity and a rapid PSA rise despite continuous AST, one could consider a randomized trial in which these men could be randomized to conventional continuous AST with or without abiraterone and/or enzalutamide.
Several points require further discussion. First, the analyses performed in this study were not prespecified and therefore are hypothesis-generating and require prospective validation. Second, men with no or minimal comorbidity were less likely to have PC with Gleason score of 8 to 10 compared to men who had moderate to severe comorbidity, as shown in Table 1, which likely reflects the practice by primary care physicians to obtain PSA for screening more often in men who are otherwise in good health as compared with those in poor health, allowing healthy men to be diagnosed earlier and therefore with lower grade disease as shown with PSA use in the PSA screening studies.[23-30] Third, a longer interval to PSA failure was associated with an increased risk of death (Table 2). Given that increased time to PSA failure is a favorable prognostic factor, one would not expect this to be due to PC deaths but competing risks. Specifically, among men with a longer interval to PSA failure (ie, > 3 years) versus a shorter interval (ie, 3 years or less, a clinically accepted cut-point) more deaths occurred (36 and 28, respectively). However, the proportion of these deaths due to PC were 5 of 36 (13.9%) patients versus 17 of 28 (60.7%) patients, respectively, indicating that most men with the longer interval to PSA failure died from causes other than PC. Fourth, men in this study received salvage AST at a PSA level of approximately 10 ng/mL, as per protocol guidelines. Whether the results of our study would have differed if salvage AST was administered at a lower PSA level or administered at the time of PSA failure requires further study. It is conceivable that earlier administration of salvage AST in men in good health may have led to lower death rate from PC; however, the significant difference in the estimates of PCSM when stratified by the median value of the PSA velocity would likely remain. Fifth, the use of salvage AST when examined as a time-dependent covariate was not significantly associated with an increased risk of death, as noted in the earlier analysis of this data. This may be explained by limited power in that of the 108 men who experienced PSA failure, 54 (50%) received salvage AST and of these 54 men, 39 died (Table 2) representing only 39 of the 64 (61%) of all observed deaths in the current study. Finally, given the advanced median age of men at PSA failure being approximately 75 and the significant toxicities associated with salvage local therapy for PSA failure, only three men with a slowly rising PSA were medically able to undergo salvage local therapy following PSA failure. In conclusion, despite unfavorable PSA kinetics at recurrence, men with moderate to severe comorbidity may not benefit from AST. RCTs examining the impact on death following intermittent AST versus surveillance are needed in these men. For men in good health and unfavorable PSA kinetics at recurrence, PC death rates are high despite continuous AST, which warrants RCTs to evaluate the impact on death of adding agents that prolong survival in men with metastatic castration-resistant PC to AST.