A phase 1/2 multicenter investigator-initiated trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

5048 Background: Dickkopf-1 (DKK1) is a secreted Wnt signaling modulator that is upregulated in prostate cancers with low androgen receptor (AR) expression and co-occurring mutations in Wnt signaling family genes. DKN-01, a potent humanized monoclonal antibody (IgG4) with neutralizing activity against DKK1, delays prostate cancer growth in pre-clinical DKK1-expressing models in an NK cell dependent manner. These data provided the rationale for a prospective clinical trial testing DKN-01 in patients with mCRPC and elevated DKK1. Here, we report the safety and efficacy results of the phase 1 dose escalation cohorts. Methods: This is an investigator-initiated parallel-arm non-randomized phase 1/2 clinical trial testing DKN-01 alone or in combination with docetaxel 75 mg/m2 for men with mCRPC who progressed on ≥1 AR signaling inhibitor. Eligible patients who had progressed on or were intolerant of docetaxel were assigned to the monotherapy cohort whereas taxane-naïve patients were assigned to the DKN-01 plus docetaxel combination cohort. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was safety, characterized by dose-limiting toxicity (DLT). A secondary endpoint of the study was to correlate anti-tumor activity, DKK1 expression (cutoff H-score ≥ 1), and clinical evidence of aggressive variant prostate cancer (AVPC). Results: 13 pts were enrolled in the completed phase 1 portion of this study – 7 patients in the monotherapy cohort and 6 patients in the combination cohort. No DLTs were observed at DKN-01 300mg or 600mg dose levels as monotherapy or in combination with docetaxel. No treatment-related serious adverse events occurred in either cohort. A best overall response of stable disease occurred in 2 out of 7 patients in the monotherapy cohort. In the combination cohort, all 5 evaluable patients had a partial response (PR) – 3 confirmed and 2 unconfirmed. All evaluable combination patients had ≥ 50% reduction in either PSA or CEA. Confirmed PRs in the combination cohort were observed in both DKK1 low (DKK1 H-score < 1) and high expressing tumors (H-score ≥1), including in 2 out of 3 patients with AVPC. Conclusions: DKN-01 600mg was well tolerated and selected as the recommended phase 2 dose as monotherapy and in combination with docetaxel. DKN-01 in combination with docetaxel showed promising clinical activity in prostate cancers regardless of DKK1 expression and was particularly promising in patients with AVPC. Further accrual into the phase 2 portion of this study is ongoing alongside preclinical and correlative studies aiming to investigate the mechanism of action of this combination therapeutic strategy. Clinical trial information: NCT03837353.