ESMO 2018: Clinical Experience of 100 Consecutive Patients Treated with Lu-177-labeled PSMA-I&T Radioligand Therapy for mCRPC

Munich, Germany (UroToday.com) Prostate-specific membrane antigen (PSMA) is a unique protein, coded on the short arm of chromosome 11, which has enzymatic activity acting as a glutamate-preferring carboxypeptidase1. PSA (prostate specific antigen) and PSMA differ in many ways, but one of the most unique features of PSMA is that PSMA expression appears to be inversely related to androgen levels and in preclinical models, PSMA activity increased as cell lines became androgen independent2

PSMA is over-expressed in all prostate tissue, including prostatic carcinoma1. Lutetium-177 (177Lu)-PSMA617 (LuPSMA) is a small radiolabeled molecule which binds to PSMA and delivers a dose of β radiation. Lutetium-177 is a good partner to help deliver the radiation because of the short range β radiation (maximal tissue penetration of <2mm), thereby decreasing the potential collateral damage to nearby organs3.

This study describes the clinical experience of 100 patients treated with 177Lu-PSMA. In terms of baseline characteristics, the median age was 72 and median PSA was 175. This was a heavily pretreated population – 57% of patients had 3 or more lines of prior therapy. 82% of patients previously had chemotherapy. This was a cohort of patients with a very aggressive disease – 33% had visceral metastases. 

ESMO 2018 Lu 177 chart 1

In terms of response, 11% of patients achieved a >90% PSA decline, with 38% achieving 50% PSA decline and 47% achieving 30% PSA decline. The median clinical progression-free survival was 4.1 months and overall survival was 12.9 months.

ESMO 2018 Lu 177 graph 1

PSA50 (PSA decline by 50%) was associated with longer clinical progression free survival and overall survival. Those patients with a PSA50 had a median OS of 10.8 months, compared to 2.9 months for those without.

ESMO 2018 Lu 177 graph 2

In terms of safety, there were no grade 3 or 4 non-hematologic toxicities, and the most common grade 3 or 4 heme toxicities were anemia (9%), thrombocytopenia (4%) and neutropenia (6%). Dry mouth is the most common non-hematologic toxicity.

ESMO 2018 Lu 177 chart 2

177Lu-PSMA appears to be a safe and active therapy for patients with mCRPC. The PSA response, progression free survival, and overall survival appear similar to that of cabazitaxel treatment for patients who progressed on docetaxel. In TROPIC, an open-label randomized phase 3 trial in men with mCRPC whose disease had progressed after docetaxel, PFS was 2.8 months (compared with 4.1 months for 177Lu-PSMA) and median overall survival was 12.7 months (compared with 12.9 months for 177Lu-PSMA)4,5. However, the toxicity profile is noticeably different – grade 3 or higher neutropenia was present in almost all patients (82%) with cabazitaxel compared to only 6% for 177Lu-PSMA. Also, 177Lu-PSMA had no grade 3 or 4 non-hematologic toxicities, but patients with cabazitaxel had several grade 3 or higher toxicities. 


Presented By: Robert L. Tauber, MD, Technische Universität München, Munich, Germany

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany.

References:

1. Chang SS. Overview of prostate-specific membrane antigen. Reviews in Urology 2004;6:S13.
2. Denmeade SR, Sokoll LJ, Dalrymple S, et al. Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. The Prostate 2003;54:249-57.
3. Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J. Lutetium 177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. Journal of medical radiation sciences 2017;64:52-60.
4. De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. The Lancet 2010;376:1147-54.
5. Pezaro CJ, Omlin AG, Altavilla A, et al. Activity of Cabazitaxel in Castration-resistant Prostate Cancer Progressing After Docetaxel and Next-generation Endocrine Agents. European Urology 2014;66:459-65.
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