Lutetium-177-PSMA-I&T as metastases directed therapy in oligometastatic hormone sensitive prostate cancer, a randomized controlled trial

Bastiaan M Privé, Marcel J R Janssen, Inge M van Oort, Constantijn H J Muselaers, Marianne A Jonker, Michel de Groot, Niven Mehra, J Fred Verzijlbergen, Tom W J Scheenen, Patrik Zámecnik, Jelle O Barentsz, Martin Gotthardt, Walter Noordzij, Wouter V Vogel, Andries M Bergman, Henk G van der Poel, André N Vis, Daniela E Oprea-Lager, Winald R Gerritsen, J Alfred Witjes, James Nagarajah, Bastiaan M Privé, Marcel J R Janssen, Inge M van Oort, Constantijn H J Muselaers, Marianne A Jonker, Michel de Groot, Niven Mehra, J Fred Verzijlbergen, Tom W J Scheenen, Patrik Zámecnik, Jelle O Barentsz, Martin Gotthardt, Walter Noordzij, Wouter V Vogel, Andries M Bergman, Henk G van der Poel, André N Vis, Daniela E Oprea-Lager, Winald R Gerritsen, J Alfred Witjes, James Nagarajah

Abstract

Background: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting.

Methods & design: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression.

Discussion: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC.

Trial registration: Clinicaltrials.gov identifier: NCT04443062 .

Keywords: Hormone sensitive prostate Cancer; Lutetium-177-PSMA; Metastases directed therapy; Oligometastases; Radioligand therapy; Urologic oncology.

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Fig. 1
Fig. 1
A scheme of the trial with the randomization and study EOT stages. EOT = End of Treatment; PSMA = prostate specific membrane antigen
Fig. 2
Fig. 2
study flowchart. CT = computed tomography; EOT = end of treatment; MRI = Magnetic resonance imaging; PET = positron emission tomography; PSA = Prostate-specific antigen; PSMA = prostate specific membrane antigen; SOC = standard of care

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.
    1. Djavan B, Moul JW, Zlotta A, Remzi M, Ravery V. PSA progression following radical prostatectomy and radiation therapy: new standards in the new millennium. Eur Urol. 2003;43(1):12–27. doi: 10.1016/S0302-2838(02)00505-5.
    1. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 2001;28(3):555–565. doi: 10.1016/S0094-0143(05)70163-4.
    1. Freedland SJ, Eastham J, Shore N. Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer. Prostate Cancer Prostatic Dis. 2009;12(4):333–338. doi: 10.1038/pcan.2009.35.
    1. Zhou P, Chen MH, McLeod D, Carroll PR, Moul JW, D'Amico AV. Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Clin Oncol. 2005;23(28):6992–6998. doi: 10.1200/JCO.2005.01.2906.
    1. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, Henry AM, Joniau S, Lam TB, Mason MD, et al. EAU-ESTRO-SIOG guidelines on prostate Cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate Cancer. Eur Urol. 2017;71(4):630–642. doi: 10.1016/j.eururo.2016.08.002.
    1. Ahmadi H, Daneshmand S. Androgen deprivation therapy: evidence-based management of side effects. BJU Int. 2013;111(4):543–548. doi: 10.1111/j.1464-410X.2012.11774.x.
    1. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, Lambert B, Delrue L, Bultijnck R, Claeys T, et al. Surveillance or metastasis-directed therapy for Oligometastatic prostate Cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446–453. doi: 10.1200/JCO.2017.75.4853.
    1. Fossati N, Suardi N, Gandaglia G, Bravi CA, Soligo M, Karnes RJ, Shariat S, Battaglia A, Everaerts W, Joniau S, et al. Identifying the optimal candidate for salvage lymph node dissection for nodal recurrence of prostate Cancer: results from a large, Multi-institutional Analysis. Eur Urol. 2019;75(1):176–183. doi: 10.1016/j.eururo.2018.09.009.
    1. Aluwini SS, Mehra N, Lolkema MP, Oprea-Lager DE, Yakar D, Stoevelaar H, van der Poel H, Busstra M, de Jong IJ, de Reijke T, et al. Oligometastatic prostate Cancer: results of a Dutch multidisciplinary consensus meeting. Eur Urol Oncol. 2019;3(2):231–8.
    1. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, Rowe SP, Ross AE, Gorin MA, Deville C, et al. Outcomes of observation vs stereotactic ablative radiation for Oligometastatic prostate Cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650–9.
    1. Schmidt-Hegemann NS, Kroeze SGC, Henkenberens C, Vogel MME, Kirste S, Becker J, Burger IA, Derlin T, Bartenstein P, Eiber M, et al. Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy-a multicenter retrospective study. Eur J Nucl Med Mol Imaging. 2020;47(8):1852–63.
    1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8–10. doi: 10.1200/JCO.1995.13.1.8.
    1. Lecouvet FE, Oprea-Lager DE, Liu Y, Ost P, Bidaut L, Collette L, Deroose CM, Goffin K, Herrmann K, Hoekstra OS, et al. Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC imaging group. Lancet Oncol. 2018;19(10):e534–e545. doi: 10.1016/S1470-2045(18)30571-0.
    1. Hofman MS, Lawrentschuk N, Francis RJ, Tang C, Vela I, Thomas P, Rutherford N, Martin JM, Frydenberg M, Shakher R, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multi-Centre study. Lancet. 2020;395(10231):1208–16.
    1. Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3(1):81–85.
    1. Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91(3):528–539. doi: 10.1002/jcb.10661.
    1. Calais J, Ceci F, Eiber M, Hope TA, Hofman MS, Rischpler C, Bach-Gansmo T, Nanni C, Savir-Baruch B, Elashoff D, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-Centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286–94.
    1. Wondergem M, Jansen BHE, van der Zant FM, van der Sluis TM, Knol RJJ, van Kalmthout LWM, Hoekstra OS, van Moorselaar RJA, Oprea-Lager DE, Vis AN. Early lesion detection with (18)F-DCFPyL PET/CT in 248 patients with biochemically recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(9):1911–1918. doi: 10.1007/s00259-019-04385-6.
    1. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, Iravani A, Kong G, Ravi Kumar A, Murphy DG, et al. [(177)Lu]-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(6):825–833. doi: 10.1016/S1470-2045(18)30198-0.
    1. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, et al. Phase 3 trial of 177Lu-Dotatate for Midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–135. doi: 10.1056/NEJMoa1607427.
    1. Heck MM, Tauber R, Schwaiger S, Retz M, D’Alessandria C, Maurer T, Gafita A, Wester H-J, Gschwend JE, Weber WA, et al. Treatment outcome, toxicity, and predictive factors for Radioligand therapy with <sup>177</sup>Lu-PSMA-I&amp;T in metastatic castration-resistant prostate Cancer. Eur Urol. 2019;75(6):920–926. doi: 10.1016/j.eururo.2018.11.016.
    1. Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, Baum RP, Kulkarni HR, Schmidt M, Drzezga A, et al. German multicenter study investigating 177Lu-PSMA-617 Radioligand therapy in advanced prostate Cancer patients. J Nuclear Med. 2017;58(1):85–90. doi: 10.2967/jnumed.116.183194.
    1. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, Davis C, Mahapane J, Corbett C, Vorster M, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46(1):129–138. doi: 10.1007/s00259-018-4167-0.
    1. van Kalmthout L, Braat A, Lam M, van Leeuwaarde R, Krijger G, Ververs T, Mehra N, Bins A, Hunting J, de Keizer B. First experience with 177Lu-PSMA-617 therapy for advanced prostate Cancer in the Netherlands. Clin Nucl Med. 2019;44(6):446–451. doi: 10.1097/RLU.0000000000002561.
    1. Hofman MS, Emmett L, Sandhu SK, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, et al. TheraP: A randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603) J Clin Oncol. 2020;38(15_suppl):5500. doi: 10.1200/JCO.2020.38.15_suppl.5500.
    1. O'Donoghue JA, Bardies M, Wheldon TE. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nuclear Med. 1995;36(10):1902–1909.
    1. Annual Congress of the European Association of Nuclear Medicine October 12–16, 2019 Barcelona, Spain. Eur J Nucl Med mol Imaging 2019, 46(1):1–952.
    1. Privé B, Peters S, Muselaers C, Zamecnik P, Janssen M, Scheenen T, Konijnenberg M, Verzijlbergen J, Gerritsen W, Mehra N, et al. Lutetium-177-PSMA-617 in low-volume hormone sensitive metastatic prostate cancer: a prospective study, vol. 59. 2020.
    1. Gillessen S, Attard G, Beer TM, Beltran H, Bossi A, Bristow R, Carver B, Castellano D, Chung BH, Clarke N, et al. Management of Patients with advanced prostate Cancer: the report of the advanced prostate Cancer consensus conference APCCC 2017. Eur Urol. 2018;73(2):178–211. doi: 10.1016/j.eururo.2017.06.002.
    1. Rahbar K, Bodei L, Morris MJ. Is the Vision of Radioligand therapy for prostate Cancer becoming a reality? An overview of the phase III VISION trial and its importance for the future of Theranostics. J Nucl Med. 2019;60(11):1504–1506. doi: 10.2967/jnumed.119.234054.
    1. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, Carducci MA, Chi KN, 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. doi: 10.1200/JCO.2015.64.2702.
    1. Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D'Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016;17(6):727–737. doi: 10.1016/S1470-2045(16)00107-8.
    1. Boorjian SA, Thompson RH, Tollefson MK, Rangel LJ, Bergstralh EJ, Blute ML, Karnes RJ. Long-term risk of clinical progression after biochemical recurrence following radical prostatectomy: the impact of time from surgery to recurrence. Eur Urol. 2011;59(6):893–899. doi: 10.1016/j.eururo.2011.02.026.
    1. Studer UE, Collette L, Whelan P, Albrecht W, Casselman J, de Reijke T, Knonagel H, Loidl W, Isorna S, Sundaram SK, et al. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891) Eur Urol. 2008;53(5):941–949. doi: 10.1016/j.eururo.2007.12.032.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner