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Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [¹⁷⁷Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

ABSTRACT:

Introduction

The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [¹⁷⁷Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with ¹⁷⁷Lu-PSMA-617.

Materials and methods

The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [¹⁷⁷Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated.

Results

The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS.

Conclusion

In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [¹⁷⁷Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

SUBMITTER: Ahmadzadehfar H

PROVIDER: S-EPMC7835179 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [<sup>177</sup>Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

Ahmadzadehfar Hojjat H Rahbar Kambiz K Baum Richard P RP Seifert Robert R Kessel Katharina K Bögemann Martin M Kulkarni Harshad R HR Zhang Jingjing J Gerke Carolin C Fimmers Rolf R Kratochwil Clemens C Rathke Hendrik H Ilhan Harun H Maffey-Steffan Johanna J Sathekge Mike M Kabasakal Levent L Garcia-Perez Francisco Osvaldo FO Kairemo Kalevi K Maharaj Masha M Paez Diana D Virgolini Irene I

European journal of nuclear medicine and molecular imaging 20200508 1

<h4>Introduction</h4>The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [<sup>177</sup>Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with <sup>177</sup>Lu-PSMA-617.<h4>Materials and ...[more]

PMID: 32383093

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Project description:BackgroundMyelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.MethodsRLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 [Formula: see text] 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 [Formula: see text] 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.ResultsSignificant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08-11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08-23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23-17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29).ConclusionHematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates.

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Project description:PurposeLutetium-177 prostate-specific membrane antigen-617 (177Lu-PSMA-617) in end-stage metastatic castration-resistant prostate cancer (mCRPC) has reported favourable outcomes. In this study, we aimed to prospectively compare the efficacy and safety of 177Lu-PSMA-617 and docetaxel in chemotherapy-naïve mCRPC patients.MethodsThis was a randomized, parallel-group, open-label, phase 2, and non-inferiority trial. Chemotherapy-naïve patients with mCRPC and high PSMA-expressing lesions on 68 Ga-PSMA-11 PET/CT were randomly assigned in 1:1 ratio to 177Lu-PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m2/cycle, every 3 weeks, up to 10 cycles). The primary end-point was best prostate-specific antigen response rate (PSA-RR), defined according to Prostate Cancer Clinical Trials Working Group-3 as proportion of patients achieving ≥ 50% decline in PSA from baseline. Non-inferiority margin of - 15% was pre-specified for PSA-RR.ResultsBetween December 2019 and March 2021, 40 of the 45 patients assessed for eligibility underwent randomization. Fifteen of 20 patients in 177Lu-PSMA-617 arm and 20/20 patients in docetaxel arm received treatment per protocol. Of these, best PSA-RR in the 177Lu-PSMA-617 arm was 60% (9/15) versus 40% (8/20) in the docetaxel arm. The difference in the PSA-RRs between the two arms was 20% (95% confidence interval, CI: - 12-47, P = 0.25), meeting the pre-specified criterion for non-inferiority in per-protocol analysis. Further, progression-free survival rates at 6 months were 30% and 20% in the 177Lu-PSMA-617 and docetaxel arms respectively (difference 10%, 95% CI: - 18-38, P = 0.50). Overall, treatment-emergent grade ≥ 3 adverse events occurred less frequently with 177Lu-PSMA-617 than with docetaxel (6/20, 30% versus 10/20, 50%, respectively, P = 0.20). Quality-of-life outcomes improved significantly in 177Lu-PSMA-617 arm compared to docetaxel arm (P < 0.01).Conclusion177Lu-PSMA-617 was demonstrated to be safe and non-inferior to docetaxel in the treatment of mCRPC and could, thus, be potentially employed earlier in the disease course rather than being solely reserved for advanced end-stage disease.Clinical trial registrationClinical Trials Registry-India, CTRI/2019/12/022282.

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Project description:BackgroundDifferentiated thyroid carcinoma (DTC) is the most common type of thyroid cancer. Treatment with surgery, radioactive iodine (RAI), and TSH suppression is effective in most patients. Five to 15% of patients become RAI refractory and need alternative therapy; however, treatment options are limited. 68Ga-PSMA PET/CT, originally developed for prostate cancer, is also applicable to other malignancies, including thyroid carcinoma. The uptake of PSMA in thyroid carcinoma gives opportunities for imaging and therapy of RAI-refractory DTC. The aim of this study was to analyze imaging on 68Ga-PSMA PET/CT and evaluate the response to 177Lu-PSMA-617 therapy in patients with RAI-refractory DTC.Materials and methodsFive patients with RAI-refractory DTC underwent 68Ga-PSMA PET/CT to determine their eligibility for 177Lu-PSMA-617 therapy. 68Ga-PSMA PET/CTs were analyzed visually and quantitatively. Response to 177Lu-PSMA-617 therapy was evaluated using imaging and thyroglobulin (Tg) values.ResultsTracer uptake suspicious for distant metastases was depicted in all 68Ga-PSMA PET/CTs. Based on tracer uptake, three patients were eligible for 177Lu-PSMA-617 therapy, of whom two were treated. One patient showed disease progression on imaging 1 month later, while her Tg values gradually increased from 18 to 63 μg/L in the months after treatment. Another patient showed partial, temporary response of lung and liver metastases. Her Tg levels initially decreased from 17 to 9 μg/L. However, 7 months after treatment, there was disease progression on imaging and Tg levels had increased to 14 μg/L. Imaging with 68Ga-PSMA PET/CT could be compared to 18FDG PET/CT in three patients. Two patients showed additional lesions on 68Ga-PSMA PET/CT, and one patient showed concordant imaging.Conclusion68Ga-PSMA PET/CT appears to have added value in patients with RAI-refractory DTC, as it is able to detect various types of lesions, some of which were not picked up by 18FDG PET/CT. Furthermore, 68Ga-PSMA PET/CT might be used to identify patients eligible for treatment with 177Lu-PSMA-617. One of the two patients who underwent 177Lu-PSMA-617 therapy showed a modest, temporary response. To draw conclusions about the effectiveness of this therapy, more research is needed.