Background: ERBB signaling is implicated in castration resistant prostate cancer (CRPC), but so far clinical trials of ERBB targeting drugs failed to demonstrate antitumor activity. We elected to re-investigate ERBB receptors in endocrine treatment-resistant lethal PC, hypothesizing that targeting ERBB receptors merits further evaluation in metastatic CRPC (mCRPC).

Design: We analyzed matching, same-patient, formalin-fixed paraffin-embedded (FFPE) treatment-naïve, castration-sensitive PC (CSPC) samples (n=88), and mCRPC biopsies (n=51), from patients treated at The Royal Marsden Hospital, UK. Samples were stained for HER2 and HER3 protein, by immunohistochemistry (IHC), data was generated through digital image analysis and results were analyzed against clinical characteristics and outcome data. Moreover, we treated HER3 high (CP50) and low (CP142) expressing patient derived xenograft (PDX) models with anti-HER3 antibody-drug conjugate (HER3-ADC) U3-1402 (10mg/Kg), IgG-ADC (MAAA-9289, 10mg/Kg), anti-HER3 antibody Patritumab (U3-1287, 10mg/Kg) and 10mM acetate buffer-5% sorbitol-pH 5.5 as vehicle control, in vitro and in vivo. In vitro cell growth inhibitory activity was monitored for 7-days with endpoint assay luminescence. In vivo efficacy was evaluated comparing tumor volumes, measured every 2-3 days. Statistical significance was analyzed using ANOVA with Dunnett’s multiple comparisons correction test.

Results: Membranous HER2 (mHER2) and HER3 (mHER3) proteins were detectable in both CSPC and mCRPC biopsies, with HER3 being highly expressed in many tumors. The median optical density (OD) for mHER3 expression at diagnosis was 2958.0; PC with high mHER3 expression (> median OD; n=44) had a significantly shorter median time to CRPC (20.3 vs 14.2 months; p=0.016) and worse overall survival (OS) (79.0 vs 48.8 months; p=0.04) compared to CSPC with low mHER3 (≤ median; n=44). mHER2 staining did not associate with outcome. U3-1402 demonstrated in vivo potent and sustained antitumor activity in CP50, without inducing any body weight loss or apparent toxicity. Additionally, no tumor regrowth was observed up to 60-days following the end of dosing. This anti-HER3-ADC had minimal antitumor activity in CP142, highlighting the relevance of high HER3 expression as a functional therapeutic target.

Conclusion: HER3 is commonly expressed in advanced PC and has clinical relevance in this setting. Our data indicate that HER3 is a valid target for clinical trials for men suffering from high HER3 expressing advanced PC.

Citation Format: Susana Miranda, Veronica Gil, Ruth Riisnaes, Bora Gurel, Mariantonietta D’Ambrosio, Alessandro Vasciaveo, Mateus Crespo, Ana Ferreira, Daniela Brina, Martina Troiani, Adam Sharp, Beshara Sheehan, Rossitza Christova, George Seed, Ines Figueiredo, Maryou Lambros, David Dolling, Jan Rekowski, Abdullah Alajati, Matthew Clarke, Rita Pereira, Penny Flohr, Gemma Fowler, Gunther Boysen, Semini Sumanasuriya, Diletta Bianchini, Pasquale Rescigno, Caterina Aversa, Nina Tunariu, Christina Guo, Alec Paschalis, Claudia Bertan, Lorenzo Buroni, Jian Ning, Suzanne Carreira, Paul Workman, Amanda Swain, Andrea Califano, Michael M. Shen, Andrea Alimonti, Antje Neeb, SU2C/PCF International Prostate Cancer Dream Team, Jonathan Welti, Wei Yuan, Johann de Bono. HER3 is an actionable target in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2807.