1118 - Post-Treatment ctDNA Alterations as Predictors of Response to <sup>177</sup>Lu-PSMA in Metastatic Castration-Resistant Prostate Cancer

08:25am - 08:30am PT

Room 155/157

Presenter(s)

Opeoluwa Akerele, BS - Tulane University School of Medicine, New Orleans, LA

O. A. Akerele¹, O. O. Pocha¹, M. Huang², A. Lieberman², J. Schwartz², P. Bhandari², A. Sartor³, and E. Ledet⁴; ¹Tulane University School of Medicine, New Orleans, LA, United States, ²Tulane School of Medicine, New Orleans, LA, ³Mayo Clinic, Rochester, MN, ⁴Tulane Cancer Center, New Orleans, LA

Purpose/Objective(s):

Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge. (Lutetium-177)¹⁷⁷Lu-PSMA-617, a radioligand therapy, has demonstrated efficacy in mCRPC, yet biomarkers predictive of therapeutic response are not well-defined. Circulating tumor DNA (ctDNA) offers a non-invasive method to evaluate tumor genomics and monitor therapeutic response in real-time. Previous studies suggest that specific ctDNA alterations correlate with response to therapy. This retrospective study evaluates ctDNA alterations in ¹⁷⁷Lu-PSMA in mCRPC patients pre- and post-treatment.

Materials/Methods:

This study included 34 mCRPC patients after receiving ¹⁷⁷Lu-PSMA. Guardant360 assay was used to evaluate ctDNA. Pre-treatment ctDNA assessment was collected averages 21 days before receiving first dose of ¹⁷⁷Lu-PSMA and after stopped previous treatment. Post-treatment ctDNA was collected 54 days after completion of ¹⁷⁷Lu-PSMA treatment to ctDNA and prior to starting a new treatment. Responder was defined as nadir PSA declined more than 50% compared to baseline PSA. Additional clinical annotation such as initial diagnosis, pathology, treatment history, and relevant germline genetic data were collected. Statistical analyses were performed with Fisher's exact and Chi-squared tests where appropriate.

Results:

Of the 34 patients who received ¹⁷⁷Lu-PSMA treatment, 19 had PSA response to ¹⁷⁷Lu-PSMA (responders) and 15 did not (non-responders). In ctDNA, copy number amplifications were significantly more frequent in non-responders (n= 14/15) when compared to responders (n= 10/19) (OR = 11.74, 95% C.I. [1.28, 588.66)], p = 0.02). Following ¹⁷⁷Lu-PSMA treatment, non-responders were also significantly more likely to have a mutated AR (OR=5.62, 95% C.I. [1.09,35.49], p=0.037), CCNE1 (OR=6.97, 95% C.I. [1.02, 83.44], p=0.025) and significantly less likely to have mutated ATM (OR=0.00, 95% C.I. [0.00, 0.45], p=0.002). All other ctDNA assessed genes were mutated at a similar frequency between responders and non-responders before and after ¹⁷⁷Lu-PSMA treatment.

Conclusion:

¹⁷⁷Lu-PSMA radioligand therapy has demonstrated the ability to extend survival and slow disease progression. Our analysis of this ¹⁷⁷Lu-PSMA-treated patient cohort suggests that distinct genomic changed detectable in ctDNA could provide insight into predicting resistance to Lu-177 treatment. Larger studies are needed to fully understand predictors of ¹⁷⁷Lu-PSMA resistance and identify genetic pathways influencing this resistance.