Therapeutic efficacy, prognostic variables and clinical outcome of 177Lu-PSMA-617 PRLT in progressive mCRPC following multiple lines of treatment: prognostic implications of high FDG uptake on dual tracer PET-CT vis-a-vis Gleason score in such cohort

Objective: To evaluate the therapeutic response, progression free survival (PFS), overall survival (OS) and clinical toxicity of Lu-177-PSMA-617 PSMA targeted radioligand therapy (PRLT) in the setting of heavily pre-treated metastatic castrate-resistant prostate cancer (mCPRC) patients and also examine the association of prognostic variables with therapeutic outcome in such patient cohort. Methods: We examined the medical records of mCRPC patients who had undergone Lu-177-PSMA-617 PRLT from March 2017 to February 2019 in our institute. Patients receiving equal to or more than two cycles were included and analyzed in this retroprospective study.The Ga-68-PSMA-11 PET-CT and 18-fludeoxyglucose positron emission tomography ((18)FDG PET)-CT scan findings, serum prostate-specific antigen (PSA) change, health-related quality of life (HROoL) scales (Eastern Cooperative Oncology Group/Karnofsky score) and Gleason score were assessed for their implications on the outcome of therapy. The treatment response was evaluated under three categories: (a) symptomatic (b) biochemical and (c) imaging response.The PFS and OS following first PRLT were determined and the association of various variables with PSA doubling time (DT) and FDG uptake in the lesions were analyzed. Toxicity assessment was undertaken objectively by National Cancer Institute-Common Terminology Criteria for Adverse Events scale v. 5.0 for haematological and nephrotoxicity, and salivary gland toxicity assessed by xerostomia inventory score. Results: A total of 40 mCRPC patients (age range: 46-84 years; median 63 years), who had undergone Lu-177-PSMA-617 PRLT, of at least two cycles was dentified and selected for the analysis. FDG uptake was noted in 87.5% of patients (n = 35). Out of 40 cases, 21 were responders (CR, PR and SD) and 19 were non-responders (PD) on symptomatic and biochemical scales while on molecular imaging response, 16 (43%) were responders and remaining 21 (57%) were non-responders. Lesion-wise, Ga-68-PSMA-11 avid metastatic nodal disease responded well with Lu-177 PSMA-617 PRLT, as compared to hepatic and skeletal lesions. The median OS and PFS was 12 and 7 months respectively following first PRLT. Patients with negative serum PSA-DT demonstrated superior 1 year PFS as compared to those with positive serum PSA-DT (52.5 vs 47.5%) (p = 0.029). Patients receiving greater than two cycles PRLT demonstrated a higher negative PSA-DT as compared to those receiving two cycles (p-value = 0.03). Grade 1 xerostomia was observed in two patients (5%) (mean xerostomia score of 23), haematotoxicity in seven patients [Grade I (n = 2, 5%) and Grade II (n = 5, 14%)]. Conclusion: Lu-177-PSMA-617 PRLT was well-tolerated and able to produce disease control with good symptomatic and biochemical responses in the context of heavily pre-treated mCRPC with progressive disease, with low toxicity profile. Evident association of high FDG uptake was observed with aggressive disease biology coupled with increasing Gleason score and poorer 12 months PFS. Negative PSA-DT following therapy demonstrated longer PFS. The results demon- strate important future role of Lu-177-PSMA-617 PRLT in the treatment of mCRPC. Advances in knowledge: The present work explored in a large teriary cancer care setting, the efficacy of (177)LuPSMA-617 PRLT, in an aggressive and unselected subset of mCRPC. The response and outcome was correlated with a number of prognostic variables, including molecular imaging findings (FDG uptake in the metastatic lesions), PSA DT and Gleason score.