Introduction: The addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival and overall survival compared to ADT alone in men with metastatic hormone-sensitive prostate cancer. Tumor resistance remains a major issue. We conducted a Phase II clinical trial enrolling men with high risk localized, locally advanced or oligometastatic prostate cancer (PC) patients to examine the feasibility and safety of surgery after neoadjuvant chemohormonal therapy, tumor response and mechanisms of resistance.
Methods: This IRB-approved single-arm trial recruited 30 patients with high risk PC. Patients received ADT and docetaxel for three cycles followed by prostatectomy. The primary endpoint was pathologic complete response and secondary PSA recurrence at 12 months. Exploratory objectives include tumor response and response heterogeneity in primary and metastatic tumors before and after treatment assessed by 18F-DCFPyL prostate specific membrane antigen (PSMA) whole body PET/MRI followed by pelvic and whole body PET/MRI as well as evaluation of gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells.
Results: To date, 26 of 30 patients have enrolled and undergone neoadjuvant treatment and radical prostatectomy (RP). Mean PSA at diagnosis was 32.1 ng/dl and 88.5% were Grade Group 5. Metastatic disease at baseline was identified in 6/26 patients (5 in lymph nodes and bone, 1 in LN only) using standard conventional imaging. Neoadjuvant therapy was well-tolerated with 24/26 completing all 3 docetaxel cycles. All patients had multi-focal primary PC detected on pretreatment PSMA pelvic PET/MRI. All patients had a decline in SUVmax after treatment in at least one lesion, but resistant tumor foci on histopathology were noted in a subset of patients. All patients underwent planned surgery (24 robotic and 2 open RP). Mean OR time was 169 minutes and mean blood loss was 226 mL. Mean length of stay was 1.6 days (range 1-7). Grade 3-4 postoperative complications are seen in 7% (2/26). On final pathology, 10 patients had node positive disease, the rate of negative surgical margins was 73%, and 80% had = pT3. No patient achieved a complete pathologic response. After follow-up of 9 months, the rate of BCR was 33.3%.
Conclusions: Definitive surgery for high risk localized and/or oligometastatic PC following neoadjuvant chemohormonal therapy generates a high rate of local tumor control. PSMA-based PET/MRI imaging showed a heterogeneity of tumor response which can potentially be used to monitor response and resistance during neoadjuvant treatment. Source of
Funding: Urology Care Foundation, Research Scholar Award (TK),PCF Young Investigator Award (C.E.K.), DOD IMPACT Award (J.M.L., D.J., D.B)