Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC).
This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination.
18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0.
DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
Prostate cancer and prostatic diseases. 2024 Feb 10 [Epub ahead of print]
David R Wise, Russell K Pachynski, Samuel R Denmeade, Rahul R Aggarwal, Jiehui Deng, Victor Adorno Febles, Arjun V Balar, Minas P Economides, Cynthia Loomis, Shanmugapriya Selvaraj, Michael Haas, Michael H Kagey, Walter Newman, Jason Baum, Andrea B Troxel, Sarah Griglun, Dayna Leis, Nina Yang, Viktoriya Aranchiy, Sabrina Machado, Erika Waalkes, Gabrielle Gargano, Nadia Soamchand, Amrutesh Puranik, Pratip Chattopadhyay, Ezeddin Fedal, Fang-Ming Deng, Qinghu Ren, Luis Chiriboga, Jonathan Melamed, Cynthia A Sirard, Kwok-Kin Wong
Department of Medicine, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. ., Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA., University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Department of Medicine, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA., Department of Pathology and DART Experimental Pathology Research Laboratory, NYU Langone Health, New York, NY, USA., Leap Therapeutics, Inc, Cambridge, MA, USA., Division of Biostatistics, Department of Population Health at NYU Grossman School of Medicine, New York, NY, USA., Precision Immunology Laboratory, Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA., Department of Pathology, New York University School of Medicine, New York, NY, USA.