Wang, Jennifer

PURPOSE Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981 ). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]

169 Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by > 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA > 90%, bone specific alkaline phosphatase > 50% and urine N-telopeptides > 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.