Abstract 5043: Radium-223 demonstrates increased antitumor activity in combination with 177Lu-PSMA-617 in the intratibial LNCaP xenograft model of bone metastatic prostate cancer

Abstract Radium-223, a bone-specific alpha particle therapy, increased survival of patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases (Parker et al., NEJM 2013) 177Lu-PSMA-617 is a small molecule radioligand that delivers beta-particle radiation to cancer cells expressing prostate-specific membrane antigen (PSMA). Despite improving overall survival of patients with heavily pretreated mCRPC (Sator et al., NEJM 2021), responses to 177Lu-PSMA-617 are often not durable and many patients develop progressive disease presumably due to microscopic osseous lesions. Compared to beta-particle radiation, alpha particles have a shorter range and higher linear energy transfer, making them more suitable for treating microscopic lesions. In this study, we evaluated preclinical antitumor efficacy and potential beneficial combination effects of radium-223 combined with 177Lu-PSMA-617 in the intratibial LNCaP xenograft model mimicking progressive prostate cancer micrometastases in bone. LNCaP prostate cancer cells were inoculated into the right tibiae of male NOD.scid mice. Six weeks after inoculation, the mice were randomized to treatment groups based on serum prostate-specific antigen (PSA) and treated with two injections (Q4Wx2, i.v.) of vehicle, radium-223 (330 kBq/kg), 177Lu-PSMA-617 (10 MBq) or their combination 177Lu-PSMA-617 was given 24 hours after radium-223. PSA and bone formation marker procollagen type I intact N-terminal propeptide (PINP) were measured from blood samples and tumor-induced abnormal bone growth was determined by radiography. Terminal blood samples were analyzed for hematologic status at sacrifice. The combination treatment of radium-223 and 177Lu-PSMA-617 demonstrated robust antitumor efficacy, as indicated by lower serum PSA (mean change relative to pretreatment levels: 63.9 % vs 631 % (vehicle control), p=0.026), decreased tumor-induced abnormal bone area in tumor-bearing tibiae (p<0.001) and suppression of abnormal bone metabolic activity as evidenced by a reduced level of the bone formation marker PINP (p<0.001), compared with vehicle. Tolerability of the combination treatment was evidenced by the lack of significant body weight loss and the absence of cumulative hematological toxicity. In conclusion, these preclinical results show that the combination of radium-223 and 177Lu-PSMA-617 is well-tolerated and efficacious in inhibiting osseous tumor growth and improving response. The combination of radium-223 and 177Lu-PSMA-I&T is currently being investigated in patients with mCRPC in a phase 1/2 trial (AlphaBet, NCT05383079). Citation Format: Arne Scholz, Matias Knuuttila, Justyna Zdrojewska, Mari I. Suominen, Esa Alhoniemi, Christoph A. Schatz, Sabine Zitzmann-Kolbe, Sanna-Maria Käkönen, Urs B. Hagemann. Radium-223 demonstrates increased antitumor activity in combination with 177Lu-PSMA-617 in the intratibial LNCaP xenograft model of bone metastatic prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5043.