A phase I/II clinical trial conducted at Oregon Health & Science University has evaluated the safety and efficacy of neoadjuvant docetaxel chemotherapy combined with radiotherapy prior to radical prostatectomy in patients with high-risk localized prostate cancer. The study, funded by Sanofi-Aventis US, was published in the American Journal of Clinical Oncology in February 2025.
The primary aim of this prospective pilot study was to assess the tolerability and preliminary efficacy of this novel neoadjuvant approach in patients with high-risk prostate cancer. The trial enrolled 25 men with localized high-risk prostate cancer, defined as having clinical stage cT2b or higher, PSA >15 ng/mL, or Gleason Grade Group 3 or greater. Exclusion criteria included prior hormonal therapy, radiation therapy, or chemotherapy for prostate cancer, as well as evidence of metastatic disease.
The study design consisted of a phase I dose-escalation portion followed by a phase II expansion cohort. In the phase I portion, patients received 45 Gy of radiotherapy to the prostate and seminal vesicles over 5 weeks, along with weekly dose-escalated docetaxel. The maximum tolerated dose was determined to be 30 mg/m2 of docetaxel weekly. In the phase II portion, 13 patients received this regimen followed by radical prostatectomy and bilateral lymph node dissection 4-6 weeks after completing neoadjuvant therapy.
The median age of participants was 62 years, and 80% of patients had clinical T-stage T2b or higher. The majority (96%) had Gleason Grade Group 3 or higher disease. The primary endpoint of pathologic complete response (pCR) was not achieved, as no patients demonstrated a pCR following surgery. However, 88% of patients achieved negative surgical margins, and the median PSA decreased by 51% following neoadjuvant therapy.
Regarding toxicity, the most common adverse events were lymphopenia, urinary frequency/urgency, diarrhea, and hyperglycemia. Grade 3-4 lymphopenia occurred in 62% of patients in the phase II portion, but there were no grade 3 or higher genitourinary or gastrointestinal toxicities observed. Three patients (12%) developed urethral stricture requiring cystoscopy, and 32% reported some degree of urinary incontinence at one year post-surgery.
Long-term outcomes were reported with a median follow-up of 11.6 years. The 10-year biochemical recurrence-free survival was 60%, and distant metastasis-free survival was 80%. Prostate cancer-specific survival and overall survival at 10 years were 84% and 60%, respectively. Univariate analyses identified pathologic T-stage and nodal stage as independent factors associated with biochemical recurrence-free survival, distant metastasis-free survival, and prostate cancer-specific mortality.
The study had several limitations, including its small sample size and single-institution design, which limit generalizability. Additionally, the trial was conducted before the advent of advanced imaging techniques like PSMA-PET/CT, which could have improved patient selection. The study also did not include androgen deprivation therapy, which is commonly used in high-risk prostate cancer treatment.
Despite not meeting the primary endpoint of pCR, the authors concluded that this neoadjuvant chemoradiation approach demonstrated a modest toxicity profile and reasonable long-term outcomes. They suggest that the regimen is feasible and safe in high-risk prostate cancer patients and could serve as a platform for combining other radio-sensitizing agents in future studies.
The potential clinical impact of this study is multifaceted. While the results do not support the immediate adoption of this specific neoadjuvant chemoradiation regimen, they provide valuable insights into the tolerability and long-term outcomes of combining radiation therapy and chemotherapy before surgery in high-risk prostate cancer. The study also highlights the need for further research to optimize endpoints and assess the efficacy of neoadjuvant treatments compared to standard approaches.
Furthermore, this trial opens the door for exploring other neoadjuvant combinations, potentially including newer agents such as novel androgen receptor-targeted therapies or immunotherapies. The long-term follow-up data provided by this study is particularly valuable, as it offers insights into the durability of treatment effects and late toxicities associated with this multimodal approach.
In conclusion, while this phase I/II trial did not demonstrate a pathologic complete response with neoadjuvant docetaxel and radiotherapy in high-risk prostate cancer, it provides important safety and long-term efficacy data that can inform future studies. As the landscape of prostate cancer treatment continues to evolve, the insights gained from this trial may contribute to the development of more effective multimodal approaches for patients with high-risk disease.
References
Ohaegbulam KC, Post CM, Farris PE, et al. Safety and Efficacy of Neoadjuvant Docetaxel and Radiotherapy in Localized High-Risk Prostate Cancer: Results From a Prospective Pilot Study. Am J Clin Oncol. 2025;48(2):75-82. doi:10.1097/COC.0000000000001151
