A secondary analysis of a randomized clinical trial has identified factors associated with shorter time to prostate-specific antigen (PSA) failure in men with nonmetastatic unfavorable-risk prostate cancer. The study, published on October 6, 2023 in JAMA Network Open, analyzed data from 350 patients enrolled in the Dana-Farber Cancer Institute 05-043 trial.
The original phase 3 trial randomized patients to receive androgen deprivation therapy (ADT) and radiation therapy (RT) with or without docetaxel. This secondary analysis aimed to evaluate factors associated with shorter time to PSA failure in order to identify patients who may benefit from treatment escalation in future clinical trials.
The study was conducted across academic and community-based health centers in the United States, Australia, and New Zealand. Funding was provided by the National Cancer Institute. Patients were enrolled between September 2005 and January 2015.
To be eligible for inclusion, patients had to have nonmetastatic unfavorable-risk prostate cancer, defined as clinical stage T1b-T4N0M0 adenocarcinoma with at least one unfavorable prognostic factor. These factors included clinical stage T2c-T4, PSA >10 ng/mL, Gleason score ≥4+3, or other high-risk features. Patients were required to be at least 30 years old with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and adequate hematologic function.
The study population included 350 men with a median age of 66 years (range 43-86). The majority were White (77.4%), with 2.6% Black and 1.1% Asian. Nearly half (46.6%) had Gleason scores of 8-10, and 55.2% had baseline PSA levels >10 ng/mL. Most patients (94.3%) had an ECOG performance status of 0.
After a median follow-up of 10.2 years, the analysis identified three significant factors associated with shorter time to PSA failure:
1. Age younger than 70 years 2. PSA level ≥10 ng/mL 3. Gleason score 8-10
Using these factors, the researchers defined a high-risk group with a 43.8% risk of PSA failure at 3 years. The cumulative incidence of PSA failure at 5 years was significantly higher in the high-risk group compared to the low-risk group (60.5% vs 29.0%, p<0.001).
In multivariable analysis, the high-risk category was associated with a subdistribution hazard ratio (sHR) of 2.69 (95% CI 1.84-3.93, p<0.001) for shorter time to PSA failure. Other factors associated with increased risk included higher clinical T stage and the use of pelvic radiotherapy.
The study had several limitations. As a secondary analysis, the results are hypothesis-generating and require validation in an independent cohort. The findings may not be applicable to treatment settings outside of those used in this study, such as post-operative settings. The high proportion of patients with good ECOG performance status may limit generalizability to populations with poorer performance status. Additionally, the study cohort was predominantly non-Hispanic White men, which may limit applicability to more diverse racial and ethnic populations.
The authors concluded that younger age (<70 years), PSA ≥10 ng/mL, and Gleason score 8-10 could be used to estimate shorter time to PSA failure following initial treatment with ADT and RT with or without docetaxel in men with nonmetastatic unfavorable-risk prostate cancer. They suggest that patients meeting these high-risk criteria may benefit from treatment escalation and should be studied in prospective randomized clinical trials.
The potential clinical impact of this study is significant. By identifying a subgroup of patients at very high risk for early PSA failure, it provides a framework for selecting patients who may benefit from treatment intensification in future clinical trials. This could lead to more personalized treatment approaches for men with unfavorable-risk prostate cancer.
The authors propose that the high-risk group identified in this study could be candidates for randomized trials evaluating treatment escalation with androgen receptor signaling inhibitors or cytotoxic chemotherapy. For example, they suggest a potential trial design where high-risk patients are randomized to ADT plus RT with or without drugs like apalutamide or darolutamide, which have shown survival benefits in non-metastatic castration-resistant prostate cancer.
It's important to note that while the addition of docetaxel to ADT and RT is not currently recommended for unfavorable-risk prostate cancer due to inconclusive results from previous trials, the subgroup identified in this study may potentially benefit from this approach and warrants further investigation.
The study also highlights the ongoing research into molecular markers for risk stratification in prostate cancer. While this analysis focused on clinical factors, future studies may incorporate tissue-based genomic tests to further refine risk assessment and treatment planning. The integration of molecular markers with clinical factors could enable even more personalized treatment approaches in the future.
In conclusion, this secondary analysis provides valuable insights into factors associated with early PSA failure in men with nonmetastatic unfavorable-risk prostate cancer. By identifying a high-risk subgroup, it lays the groundwork for future clinical trials investigating treatment intensification strategies. As with all secondary analyses, these findings require validation in prospective studies before they can be applied to clinical practice. Nonetheless, they represent an important step towards more personalized and effective treatments for men with high-risk prostate cancer.
References
Sayan M, Huang J, Xie W, et al. Risk of Short-Term Prostate-Specific Antigen Recurrence and Failure in Patients With Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023;6(10):e2336390. Published 2023 Oct 2. doi:10.1001/jamanetworkopen.2023.36390
