Preliminary phase 2 results of PT-112 monotherapy in late-line metastatic castration-resistant prostate cancer (mCRPC).

5071 Background: Late-line mCRPC has shown poor outcomes as a result of disease heterogeneity, metastases in bone and viscera including liver, and limited immunotherapeutic options. PT-112 is a novel therapy that inhibits ribosome biogenesis, induces robust immunogenic cell death, concentrates in bone and soft tissue, and previously exhibited clinical activity in patients (pts) with mCRPC. We report the results of a Phase 2 study of monotherapy PT-112 in the late-line mCRPC population. Methods: mCRPC pts with ≥3 prior standard of care treatments, including ≥1 androgen receptor pathway inhibitor (ARPI) and 1-2 taxanes with radiographic progression at entry were randomized to one of three dosing arms: Arm 1 (360 mg/m² Q2W), Arm 2 (250 mg/m² Q2W), and Arm 3 (360 mg/m² Q2W in cycle 1, then 250 mg/m² D15 of subsequent 28-day cycles). The primary endpoint was to determine the optimal dosing regimen based on safety and efficacy per FDA Project Optimus. Results: Pts on the study (N=111) had a median of 4 prior lines of therapy, 69% with ≥2 ARPis, 59% with 2 taxanes, and 24% with PSMA-Lu-177. At entry, pts had liver metastases (19%), bone-only metastases (28%), and evidence of bone progression (74%). The most common treatment-related adverse events (TRAEs) were fatigue (53%), nausea (42%), and anemia (41%); no G5 TRAEs. Discontinuation due to AEs was 12%. Due to superior balance of efficacy and tolerance at interim analysis, Arms 2 and 3 proceeded to full enrollment, while Arm 1 was discontinued. Safety and efficacy metrics are summarized in Table 1. In the more mature Arm 2, OS in pts without prior cabazitaxel (22 pts) was 16.4m and without cabazitaxel or PSMA-Lu-177 (17 pts) was 20.5m. 4% of pts had confirmed PCWG3 bone progression on study. A signal of immune response was observed via TCR sequencing with a statistically significant 20% increase in the percentage of TCR+ blood cells. Conclusions: PT-112 treatment resulted in a manageable and reasonably low rate of G3-4 TRAEs and was active in pts with very late-line mCRPC. The better balance of safety and efficacy in Arms 2 and 3 is indicative of an optimized RP3D. Biomarker responses (ALP, CTC and T cell) may reflect broad activity of PT-112. ctDNA analyses are ongoing. OS duration in these heavily pretreated patients, with low rates of bone progression and symptomatic skeletal events (SSEs) on study, are encouraging and supportive of a Phase 3 study of PT-112 vs standard of care. Clinical trial information: NCT02266745 . Study metrics. Metric Arm 1 (n=19) Arm 2 (n=46) Arm 3 (n=46) All Pts (N=111) G3-4 TRAEs (% of pts) 47 27 43 37 Adherence of dose regimen for first 2 cycles (% of pts) 42 59 67 59 Disease control rate (SD, PR, or CR) at 4 months (% of pts) 27 28 18 23 Median OS (m) 9.0 9.7 10.0 9.7 Median rPFS (m) 3.6 2.5 3.4 3.4 PSA50 (% of pts) 5 17 12 13 CTC0 (n, % of pts) 3/15 (20%) 5/22 (23%) 8/15 (53%) 16/52 (31%) ≥10% ALP decline (% of pts) 74 41 56 52 SSEs in first 4 months (% of pts) 16 4 2 5