Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer

Abstract

Objective To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55–84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee.

Results A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one.

Conclusion PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

Zusammenfassung

Ziel Es sollte der klinische Nutzen der Lu-177-PSMA-617-Radioligandentherapie bei Patienten mit metastasiertem kastrationsresistentem Prostatakrebs (mCRPC) untersucht werden.

Patienten und Methoden In diese retrospektive Analyse zwischen November 2014 und Dezember 2018 wurden insgesamt 56 konsekutive Patienten (medianes Alter 69,5 Jahre; Bereich 55–84 Jahre) mit mCRPC eingeschlossen. Die Patienten erhielten zwischen 1 und 4 Therapiezyklen mit einer mittleren Aktivität von 6,8 GBq pro Zyklus. Das biochemische Ansprechen wurde anhand der Kriterien der „Prostate Cancer Working Group“ (PCWG 3) bewertet. Das Überleben wurde mittels Kaplan-Meier-Schätzer und einer proportionalen Cox-Hazard-Regressionsanalyse bewertet. Diese retrospektive Studie wurde von der zuständigen Ethikkommission genehmigt.

Ergebnisse Insgesamt wurden 139 Behandlungszyklen mit Lu-177-PSMA-617 durchgeführt. Eine Abnahme des Prostata-spezifischen Antigens (PSA) um 50 % oder mehr trat bei 54 % und eine PSA-Abnahme in beliebiger Höhe bei 65 % der Patienten auf. Das geschätzte mediane Gesamtüberleben (OS) betrug 16 Monate, in der Chemotherapie-Untergruppe 14 Monate. Ein längeres OS war verbunden mit einem PSA-Abfall ≥50%, mehr als 2 Therapiezyklen, einer kumulativen Aktivität >15 GBq und einem initialen Wert für alkalischen Phosphatase ≤220 [U/l]. Diese identifizierten Prädiktoren blieben in der uni- und multivariaten Cox-Regressionsanalyse signifikant. Außerdem wurden 40 % der Patienten, die nach dem ersten Therapiezyklus nicht auf die Therapie ansprachen (Non-Responder), nach dem zweiten Zyklus zu Respondern.

Schlussfolgerung Ein PSA-Abfall von ≥50%, eine kumulative Aktivität von >15 GBq und ein initialer Wert für alkalische Phosphatase von ≤220 [U/l] wurden als Schlüsselprädiktoren für ein längeres OS bei Patienten mit mCRPC identifiziert. Im Gegensatz dazu führte eine rasche klinische Verschlechterung, meist aufgrund einer Skelettkarzinose, zu einem frühen Therapieversagen.

Schlüsselwörter

Prostatakarzinom - Lu-177-PSMA-617 - Radioligandentherapie

Keywords

prostate carcinoma - Lu-177-PSMA-617 - radioligand therapy

Publication History

Received: 09 June 2021

Accepted after revision: 14 October 2021

Article published online:
16 December 2021

• Literature

• 1 Assadi M, Rezaei S, Jafari E. et al. Potential application of lutetium-177-labeled prostate-specific membrane antigen-617 radioligand therapy for metastatic castration-resistant prostate cancer in a limited resource environment: Initial clinical experience after 2 years. World J Nucl Med 2020; 19 (01) 15-20 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067127/
• 2 Heck MM, Retz M, DʼAlessandria C. et al. Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer. J Urol 2016; 196 (02) 382-391 DOI: 10.1016/j.juro.2016.02.2969. (PMID: 26964917)
• 3 Mayor N, Sathianathen NJ, Buteau J. et al. Prostate-specific membrane antigen theranostics in advanced prostate cancer: an evolving option. BJU Int 2020; 126 (05) 525-535 DOI: 10.1111/bju.15143. (PMID: 32559353)
• 4 Seifert R, Kessel K, Schlack K. et al. Radioligand therapy using [177Lu]Lu-PSMA-617 in mCRPC: a pre-VISION single-center analysis. Eur J Nucl Med Mol Imaging 2020; 47: 2106-2112 DOI: 10.1007/s00259-020-04703-3. (PMID: 32062682)
• 5 Violet J, Sandhu S, Iravani A. et al. Long term follow-up and outcomes of re-treatment in an expanded 50 patient single-center phase II prospective trial of Lutetium-177 (177Lu) PSMA-617 theranostics in metastatic castrate-resistant prostate cancer. J Nucl Med 2019; DOI: 10.2967/jnumed.119.236414.
• 6 Yadav MP, Ballal S, Bal C. et al. Efficacy and Safety of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients. Clin Nucl Med 2020; 45 (01) 19-31 DOI: 10.1097/RLU.0000000000002833. (PMID: 31789908)
• 7 Rahbar K, Bode A, Weckesser M. et al. Radioligand Therapy With 177Lu-PSMA-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer. Clin Nucl Med 2016; 41 (07) 522-528 DOI: 10.1097/RLU.0000000000001240. (PMID: 27088387)
• 8 Scher HI, Morris MJ, Stadler WM. et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 2016; 34 (12) 1402-1418
• 9 Fendler WP, Kratochwil C, Ahmadzadehfar H. et al. Therapie mit 177Lu-PSMA-617, Dosimetrie und NAchsorge beim metastasierten kastrationsresistenten Prostatakarzinom. Nuklearmedizin 2016; 55: 123-128
• 10 Ahmadzadehfar H, Rahbar K, Baum RP. et al. 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). Eur J Nucl Med Mol Imaging 2021; 48 (01) 113-122 DOI: 10.1007/s00259-020-04797-9. (PMID: 32383093)
• 11 Rahbar K, Schmidt M, Heinzel A. et al. Response and tolerability of a single dose of 17Lu-PSMA-617 in patients wih metastatic castration-resistant prostate cancer: a multicenter retrospective analysis. J Nucl Med 2016; 57: 1334-1338
• 12 Kratochwil C, Giesel FL, Stefanova M. et al. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with 177Lu-labeled PSMA-617. J Nucl Med 2016; 57: 1170-1176 DOI: 10.2967/jnumed.115.171397. (PMID: 26985056)
• 13 Rahbar K, Boegemann M, Yordanova A. et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival. Eur J Nucl Med Mol Imaging 2018; 45: 12-19 DOI: 10.1007/s00259-017-3848-4. (PMID: 29026946)
• 14 Hofman MS, Violet J, Hicks RJ. et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol 2018; 19: 825-833
• 15 Hofman MS, Emmett L, Sandhu S. et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. The Lancet 2021; DOI: 10.1016/S0140-6736(21)00237-3.
• 16 Sartor O, de Bono J, Chi KN. et al. for the VISION Investigators. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; DOI: 10.1056/NEJMoa2107322.
• 17 Baum RP, Kulkarni HR, Schuchardt C. et al. 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. J Nucl Med 2016; 57: 1006-1013 DOI: 10.2967/jnumed.115.168443. (PMID: 26795286)
• 18 Heck MM, Tauber R, Schwaiger S. et al. Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with 177Lu-PSMA-I&T in Metastatic Castration-resistant Prostate Cancer. Eur Urol 2019; 75 (06) 920-926 http://www.sciencedirect.com/science/article/pii/S030228381830873X
• 19 Tagawa ST, Batra J, Vallabhajosula S. et al. Final results of 2-dose fractionation of 177Lu-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2016; 34 (Suppl. 15) 5022 https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.5022
• 20 Tannock IF, de Wit R, Berry WR. et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N Engl J Med 2020; 351 (15) 1502-1512 DOI: 10.1056/NEJMoa040720. (PMID: 15470213)
• 21 von Eyben FE, Roviello G, Kiljunen T. et al. Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging 2018; 45 (03) 496-508 DOI: 10.1007/s00259-017-3895-x. (PMID: 29247284)
• 22 De Bono JS, Logothetis CJ, Molina A. et al. for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995-2005 DOI: 10.1056/NEJMoa1014618. (PMID: 21612468)
• 23 Soydal C, Araz M, Urun Y. et al. Prognostic importance of PSA response in patients who received Lutetium-177 PSMA treatment for castration resistant prostate cancer. Q J Nucl Med Mol Imaging 2019; DOI: 10 DOI: 10.23736/S1824-4785.19.03165-0. (PMID: 31602963)
• 24 Ahmadzadehfar H, Schlolaut S, Fimmers R. et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand therapy. Oncotarget 2017; 8 (61) 103108-103116 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732715/ DOI: 10.18632/oncotarget.21600. (PMID: 29262549)
• 25 Bräuer A, Grubert LS, Roll W. et al. 177Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 2017; 44 (10) 1663-1670 DOI: 10.1007/s00259-017-3751-z. (PMID: 28624848)
• 26 Rahbar K, Ahmadzadehfar H, Kratochwil C. et al. German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. J Nucl Med 2017; 58 (01) 85-90 DOI: 10.2967/jnumed.116.183194. (PMID: 27765862)
• 27 Gafita A, Fendler WP, Hui W. et al. Efficacy and safety of 177Lu-labelled Prostate-specific membrane antigen radionuclide treatment in patients with diffuse bone marrow involvement: a multicenter retrospective study. Eur Urology 2019; DOI: 10.1016/j.eururo.2020.05.004.
• 28 Thang SP, Violet J, Sandhu S. et al. Poor Outcomes for Patients with Metastatic Castration-resistant Prostate Cancer with Low Prostate-specific Membrane Antigen (PSMA) Expression Deemed Ineligible for 177Lu-labelled PSMA Radioligand Therapy. Eur Urol Oncol 2019; 2 (06) 670-676 DOI: 10.1016/j.euo.2018.11.007. (PMID: 31412006)
• 29 Ahmadzadehfar H, Rahbar K, Kürpig S. et al. Early side effects and first results of radioligand therapy with 177Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. Eur J Nucl Med Mol Imaging Res 2015; 5: 36 DOI: 10.1186/s13550-015-0114-2.
• 30 Violet JA, Jackson P, Ferdinandus J. et al. Dosimetry of Lu-177-PSMA-617 in metastatic castration-resistant prostate cancer: correlations between pre-therapeutic imaging and “whole body” tumor dosiemtry with treatment outcomes. J Nucl Med 2018; DOI: 10.2967/jnumed.118.219352.
• 31 Scher HI, Fizazi K, Saad F. et al. for the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-1197 DOI: 10.1056/NEJMoa1207506. (PMID: 22894553)
• 32 Seifert R, Kessel K, Schlack K. et al. PSMA PET total tumor volume predicts outcome of patients with advanced prostate cancer receiving [177Lu]Lu-PSMA-617 radioligand therapy in a bicentric analysis. Eur J Nucl Med Mol Imaging 2021; 48 (04) 1200-1210 DOI: 10.1007/s00259-020-05040-1. (PMID: 32970216)