Introduction:

Previous studies have shown that addition of docetaxel to standard androgen deprivation therapy (ADT) significantly improves progression-free survival (PFS) and overall survival (OS) compared to standard ADT alone in men with metastatic hormone-sensitive prostate cancer. Further evidence suggest that removal of the primary may improve outcomes by reducing the risk of tumor self-seeding.  Tumor resistance remains a major issue in the treatment of advanced cancer.  We are conducting a Phase II trial enrolling men with very high risk localized, locally advanced or oligometastatic prostate cancer (PC) patients to examine the feasibility of neoadjuvant chemohormonal therapy, tumor response and molecular mechanisms of resistance.

Methods:

UW17009 is an IRB-approved open-label, single-arm trial recruiting 30 patients with newly diagnosed locally advanced PC.  Patients receive ADT and docetaxel for three cycles (3 months) followed by prostatectomy. The primary endpoint is pathologic complete response rates. Secondary clinical objectives are rate of patients with PSA recurrence at month 12 after surgery as well as safety and tolerability. Exploratory interventions include PSMA PET/MRI imaging as a method for determining treatment response and response heterogeneity in primary prostate cancer and metastatic lesions performed before and after chemohormonal therapy.  In addition, evaluation of genomic and gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells in responding and resistant lesions is ongoing.

Results:

To date, 26 of 30 patients have enrolled and undergone neoadjuvant treatment and radical prostatectomy (RP) with lymph node dissection. The mean age is 61 year, 96% are Caucasian with mean BMI of 28.35. The mean PSA at diagnosis was 32.1 ng/dl and 88.5% had Grade Group 5 cancer. All patients had multi-focal PC at baseline with 23/26 with Gleason 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 overall well tolerated with expected toxicities including fatigue and neutropenia. All but two patients received all 3 cycles of docetaxel chemotherapy. All patients had multi-focal primary PC detected on PSMA PET/MRI. All patients underwent planned surgery (24 robotic and 2 open RP). Mean OR time was 169 minutes and mean estimated blood loss was 226 mL. One patient received a blood transfusion following open RP. Mean length of stay was 1.6 days (1-7 days). Grade 3-4 postoperative complications were seen in 7% (2/26). Mean number of lymph nodes removed was 13.4 and ten patients had node positive disease. The rate of negative surgical margins was 73% and 80% of patient had ≥ pT3 on final pathology. No patient achieved a complete pathologic response, however 91% (24/26) had undetectable PSA on week 6 after surgery. The two patients with persistent PSAs following surgery received salvage ADT with Abiraterone. Mean follow-up is 8 months (1.6-12 months) and rate of biochemical failure 23% (6/26).

Conclusion:

Neoadjuvant chemohormonal therapy prior to definitive surgery for very high risk localized and/or oligometastatic PC generates a high rate of local tumor control with a heterogeneity of tumor response between foci. The treatments are well tolerated with side effects similar to those previously described with chemohormonal therapy.  Further characterization of tumor heterogeneity and molecular imaging is ongoing.

Funding: Urology Care Foundation, Research Scholar Award (TK), The 2016 Debbie and Mark Attanasio-PCF Young Investigator Award (C.E.K.), DOD IMPACT Award 191341- Partnering PI (J.M.L., D.J., D.B)