Abstract
Background
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).
Methods
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.
Results
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.
Conclusion
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.
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Data availability
The data on which the conclusions of the paper rely are presented in the main manuscript and the additional supporting material.
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Acknowledgements
We acknowledge the patients, their families, and caregivers for their participation in this study. We acknowledge the NYULH Center for Biospecimen Research and Development (RRID: SCR_017930) and Histology and Immunohistochemistry Laboratory (RRID:SCR_018304) supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant; NIH/NCI P30CA016087. This work was supported in part by a Prostate Cancer Foundation Young Investigator Award E2457556 to DRW.
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Conceptualization: DRW, JD, AVB, MHK, WN, ABT, PC, CA, KKW. Collection and assembly of data: DRW, RKP, SRD, RRA, JD, VAF, CL, SS, SG, DL, NY, VA, SM, EW, GG, NS, AP, EF, FD, QR, LC, JM. Data analysis and interpretation: DRW, RKP, JD, AVB, MH, MHK, WN, JB, ABT, AP, PC, FMD, JM, CA. Paper writing-original draft: DRW, JB, CA. Paper review and editing: All authors.
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DRW is a paid consultant for Leap Therapeutics, Foundation Medicine, Pfizer, Janssen, Sanofi, Lilly, Labcorp, Myovant, Bayer, AstraZeneca, Accutar. He has received travel funding from Pfizer and Bayer.
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Wise, D.R., Pachynski, R.K., Denmeade, S.R. et al. A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00798-z
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DOI: https://doi.org/10.1038/s41391-024-00798-z