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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 and Prostatic Diseases (2024)Cite this article

Subjects

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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Fig. 1: Treatment emergent adverse events.
Fig. 2: Efficacy.
Fig. 3: DKK1 Expression and correlative analysis.

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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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Authors and Affiliations

  1. Department of Medicine, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA

    David R. Wise, Jiehui Deng, Victor Adorno Febles, Arjun V. Balar, Minas P. Economides, Sarah Griglun, Dayna Leis, Nina Yang, Viktoriya Aranchiy, Sabrina Machado, Erika Waalkes, Gabrielle Gargano, Nadia Soamchand, Amrutesh Puranik & Kwok-Kin Wong

  2. Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

    Russell K. Pachynski

  3. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA

    Samuel R. Denmeade

  4. University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

    Rahul R. Aggarwal

  5. New York Harbor Veterans Healthcare System, New York, NY, USA

    Victor Adorno Febles

  6. Department of Pathology and DART Experimental Pathology Research Laboratory, NYU Langone Health, New York, NY, USA

    Cynthia Loomis & Shanmugapriya Selvaraj

  7. Leap Therapeutics, Inc, Cambridge, MA, USA

    Michael Haas, Michael H. Kagey, Walter Newman, Jason Baum & Cynthia A. Sirard

  8. Division of Biostatistics, Department of Population Health at NYU Grossman School of Medicine, New York, NY, USA

    Andrea B. Troxel

  9. Precision Immunology Laboratory, Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA

    Amrutesh Puranik & Pratip Chattopadhyay

  10. Department of Pathology, New York University School of Medicine, New York, NY, USA

    Ezeddin Fedal, Fang-Ming Deng, Qinghu Ren, Luis Chiriboga & Jonathan Melamed

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Contributions

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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Correspondence to David R. Wise.

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Competing interests

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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