Abstract 1393: PSMA-Targeted Thorium Conjugate (BAY 2315497) and olaparib combination show synergistic anti-tumor activity in prostate cancer models
Authors: Schatz Christoph A. , Hammer Stefanie , Wengner Antje , Hagemann Urs B. , Mumberg Dominik , Scholz Arne 
Published: July 2021

Abstract
The PSMA targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) is a novel targeted alpha therapy (TAT) approach which is currently under investigation in a FiH trial in patients with metastatic castration resistant prostate cancer (mCRPC; NCT03724747). It consists of the alpha emitter thorium-227 complexed to a 3,2-HOPO chelator conjugated to a PSMA targeting antibody delivering radiation to PSMA expressing tumor cells and their microenvironment resulting in the induction of potentially cytotoxic DNA double-strand breaks (DBS). Combining with the PARP inhibitor olaparib may act synergistically via inhibition of DDR pathways. Here we evaluated the efficacy of PSMA-TTC in combination with olaparib that demonstrated a positive outcome in patients with homologous recombination repair-mutated mCRPC. We explored potential synergies of the combination treatment in prostate cancer models in vitro and in vivo and studied the mode of action by protein and RNA analysis. In vitro, synergy of the combination of PSMA-TTC with olaparib with a combination index (CI) of 0.7 was observed in three cell lines, namely LNCaP, 22Rv1 and MDA-PCa2b. with the first two (LNCaP and 22Rv1) carrying mutations in BRCA2. Only moderate synergy with a CI of 0.8 was seen in BRCA2 wt VCaP cells. In vivo, dose dependent anti-tumor activity with single i.v. injections of PSMA-TTC at 150 and 300 kBq/kg was seen in the LNCaP prostate cancer model resulting in a tumor/control (T/C) ratio of 0.3 and 0.09 at day 28, respectively. In contrast, olaparib given at 50 mg/kg QD did not show activity at day 28. The 300 kBq/kg PSMA-TTC dose combined with olaparib showed the most pronounced anti-tumor activity (T/C=0.04) and significantly increased the number of animals with complete tumor regressions compared to high dose PSMA-TTC alone (6 CRs vs 2 CRs, p = 0.0397, Chi-square) on day 28. At the end of the consecutive surveillance period on day 117, 7/8 (87.5%) animals remained tumor-free (putatively cured) in the combination group vs 4/10 (40%) mice in the PMSA-TTC monotherapy group (Chi-square test, P = 0.0400). Additive or synergistic toxicological effects for the combination treatment were not seen based on body weight loss and fatal tox rate. At the 117-day time point both the 300 kBq/kg PSMA-TTC monotherapy and combination with olaparib group demonstrated 0.3% and 9.3% body weight gain indicating good tolerability. Changes in markers of DNA damage response following treatment will be presented. In summary, combination of PSMA-TTC with olaparib shows synergistic preclinical anti-tumor activity and support further clinical investigation of this combination treatment in prostate cancer patients.
Citation Format: Christoph A. Schatz, Stefanie Hammer, Antje Wengner, Urs B. Hagemann, Dominik Mumberg, Arne Scholz. PSMA-Targeted Thorium Conjugate (BAY 2315497) and olaparib combination show synergistic anti-tumor activity in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1393.