Anti-Androgen Therapy Overcomes the Time Delay in Initiation of Salvage Radiation Therapy and Rescues the Oncological Outcomes in Men with Recurrent Prostate Cancer After Radical Prostatectomy: A Post Hoc Analysis of the RTOG-9601 Trial Data

Abstract

Background It is unknown whether the addition of anti-androgen therapy (AAT) to late salvage radiation therapy (sRT) can lead to oncological outcomes equivalent to that of early sRT in men with recurrent prostate cancer (CaP) after surgery. Methods Data on 670 men who participated in the Radiation Therapy Oncology Group (RTOG)-9601 trial and who experienced biochemical recurrence were extracted using the National Clinical Trials Network (NCTN) data archive platform. Patients were stratified into four treatment groups: early sRT (pre-sRT prostate-specific antigen [PSA] < 0.7 ng/mL) and late sRT (pre-sRT PSA ≥ 0.7 ng/mL) with/without concomitant AAT, based on cut-offs reported in the original trial. Time-varying Cox proportional hazards and Fine–Gray competing-risk regression analyses assessed the adjusted hazards of overall mortality, CaP-specific mortality, and metastasis among the four treatment groups. Results At 15-years (median follow-up of 14.7 years), for patients treated with early sRT, early sRT with AAT, late sRT, and late sRT with AAT, the overall mortality, CaP-specific mortality, and metastasis rates were 22.9, 22.8, 40.1, and 22.9% (log-rank p = 0.0039), 12.1, 3.9, 22.7, and 8.0% (Gray’s p = 0.0004), and 18.8, 14.6, 35.9, and 19.5% (Gray’s p = 0.0004), respectively. Time-varying multivariable adjusted analysis demonstrated increased hazards of overall mortality in patients receiving delayed sRT versus early sRT (hazards ratio [HR] 1.49, 95% confidence interval [CI] 1.02–2.17); however, no difference remained after the addition of concomitant AAT to late sRT (HR 0.85, 95% CI 0.55–1.32, referent early sRT). Likewise, the hazards of cancer-specific mortality and metastatic progression were worse for late sRT when compared with early sRT, but were no different after the addition of AAT to late sRT. Conclusions Poorer outcomes associated with late sRT in men with recurrent CaP may be rescued by delivery of concomitant AAT.

Review of Current Treatment Intensification Strategies for Prostate Cancer Patients

“…The latest data highlight the application of treatment intensification (TI) for high-risk patients with localized PCa [30]. TI refers to the use of more advanced therapies to manage the disease when standard treatments are insufficient or when PCa recurs.…”

Prostate Cancer: Advances in Radiation Oncology, Molecular Biology, and Future Treatment Strategies

“…There is evidence that additional therapy coupled with radiation therapy improves clinical outcome in patients with unfavorable intermediate risk and high-risk prostate cancer (36,37). For example, multiple forms of hormone therapy coupled with radiation therapy has demonstrated improvements in clinical outcome for intermediate and high-risk patients (3,36,37).…”

“…There is evidence that additional therapy coupled with radiation therapy improves clinical outcome in patients with unfavorable intermediate risk and high-risk prostate cancer (36,37). For example, multiple forms of hormone therapy coupled with radiation therapy has demonstrated improvements in clinical outcome for intermediate and high-risk patients (3,36,37). However, despite the advantage in patient care and outcome, the duration of hormone therapy, the impact of hormone on normal tissue, and the quality of life remain understudied.…”

“…In the past, multiple agents have been approved for patient care in prostate cancer, many directed towards androgen-directed pathways including the androgen receptor. Abiraterone acetate (Zytiga), apalutamide (Erleada), orgovyx (Regugolix), and enzalutamide (Xtandi) are new approaches to patient care directed towards androgen inhibition (37)(38)(39)(40)(41)(42). While currently used for recurrent disease, studies are now needed to determine if these medications can function as a surrogate for traditional hormone therapy in primary management with the objective of limiting the sequelae seen with Lupron therapy.…”

“…These areas remain less well defined and are of important clinical relevance to patient care and quality of life. Radium 223, sipuleucel T immunotherapy, and more traditional chemotherapy with Docetaxol have been used in patients with advanced disease with and without hormone therapy, often with limited success due in part to previous treatments and limitations in patient normal tissue reserves (37)(38)(39)(40)(41)(42). Leutium 177 ligand is a novel radiopharmacy tool, FDA approved, which delivers beta particle radiation therapy to PSMA expressing cells and the immediate microenvironment.…”