A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS)

Hamza Hasan, Matthew P Deek, Ryan Phillips, Robert F Hobbs, Reem Malek, Noura Radwan, Ana P Kiess, Shirl Dipasquale, James Huang, Terry Caldwell, Jessica Leitzel, Danielle Wendler, Hao Wang, Elizabeth Thompson, Jonathan Powell, Sara Dudley, Curtiland Deville, Stephen C Greco, Daniel Y Song, Theodore L DeWeese, Michael A Gorin, Steven P Rowe, Sam Denmeade, Mark Markowski, Emmanuel S Antonarakis, Michael A Carducci, Mario A Eisenberger, Martin G Pomper, Kenneth J Pienta, Channing J Paller, Phuoc T Tran, Hamza Hasan, Matthew P Deek, Ryan Phillips, Robert F Hobbs, Reem Malek, Noura Radwan, Ana P Kiess, Shirl Dipasquale, James Huang, Terry Caldwell, Jessica Leitzel, Danielle Wendler, Hao Wang, Elizabeth Thompson, Jonathan Powell, Sara Dudley, Curtiland Deville, Stephen C Greco, Daniel Y Song, Theodore L DeWeese, Michael A Gorin, Steven P Rowe, Sam Denmeade, Mark Markowski, Emmanuel S Antonarakis, Michael A Carducci, Mario A Eisenberger, Martin G Pomper, Kenneth J Pienta, Channing J Paller, Phuoc T Tran

Abstract

Background: Metastasis directed therapy (MDT) for patients with oligometastatic disease is associated with improvements in progression free survival (PFS) and overall survival (OS) compared to systemic therapy alone. Additionally, within a prostate-cancer-specific cohort, MDT is able to forestall initiation of androgen deprivation therapy (ADT) in men with hormone-sensitive, oligometastatic prostate cancer (HSOPCa) compared to observation. While MDT appears to be safe and effective in HSOPCa, a large percentage of men will eventually have disease recurrence. Patterns of failure in HSOPCa demonstrate patients tend to have recurrence in the bone following MDT, raising the question of sub-clinically-apparent osseous disease. Radium-223 dichloride is a radiopharmaceutical with structural similarity to calcium, allowing it to be taken up by bone where it emits alpha particles, and therefore might have utility in the treatment of micrometastatic osseous disease. Therefore, the primary goal of the phase II RAVENS trial is to evaluate the efficacy of MDT + radium-223 dichloride in prolonging progression free survival in men with HSOPCa.

Methods: Patients with HSOPCa and 3 or less metastases with at least 1 bone metastasis will be randomized 1:1 to stereotactic ablative radiation (SABR, also known as stereotactic body radiation therapy (SBRT)) alone vs SABR + radium-223 dichloride with a minimization algorithm to balance assignment by institution, primary intervention, prior hormonal therapy, and PSA doubling time. SABR is delivered in one to five fractions and patients in the SABR + radium-223 dichloride arm will receive six infusions of radium-223 dichloride at four-week intervals. The primary end point is progression free survival. The secondary clinical endpoints include toxicity and quality of life assessments, local control at 12 months, locoregional progression, time to distant progression, time to new metastasis, and duration of response.

Discussion: The RAVENS trial will be the first described phase II, non-blinded, randomized study to compare SABR +/- radium-223 dichloride in patients with HSOPCa and 3 or less metastases with at least one bone metastasis. The primary hypothesis is that SABR + radium-223 dichloride will increase median progression-free survival from 10 months in the SABR arm to 20 months in the SABR + radium-223 dichloride arm.

Trial registrations: Clinicaltrials.gov. Identifier: NCT04037358. Date of Registration: July 30, 2019. Date of First Participant Enrolled: August 9, 2019. Date of Last Approved Amendment: October 16, 2019. Protocol Version: Version 5.

Keywords: Bone; Cancer; Metastasis; Oligometastatic; Prostate; Radium-223; Stereotactic ablative radiation (SABR).

Conflict of interest statement

Robert Hobbs is a consultant for Radiopharmaceutical Imaging and Dosimetry LLC (RAPID).

Figures

Fig. 1
Fig. 1
Trial Schema

References

    1. Moinpour CM, Savage MJ, Troxel A, et al. Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst. 1998;90:1537–1544.
    1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13:8–10.
    1. Bacci G, Rocca M, Salone M, et al. High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol. 2008;98:415–420.
    1. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer. 2006;94:982–999.
    1. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15:938–946.
    1. Steele G, Jr, Bleday R, Mayer RJ, Lindblad A, Petrelli N, Weaver D. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: gastrointestinal tumor study group protocol 6584. J Clin Oncol. 1991;9:1105–1112.
    1. Deek MP, Yu C, Phillips R, et al. Radiation therapy in the definitive Management of Oligometastatic Prostate Cancer: the Johns Hopkins experience. Int J Radiat Oncol Biol Phys. 2019;105:948–956.
    1. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative radiotherapy for limited metastatic non-small-cell lung Cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2018;4:e173501.
    1. Gomez DR, Blumenschein GR, Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17:1672–1682.
    1. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393:2051–2058.
    1. Phillips RM, Hayman J, Tran PT. STOMPing out hormone-sensitive metastases with local therapies in prostate Cancer. J Clin Oncol. 2018;36:435–437.
    1. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for Oligometastatic prostate Cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36:446–453.
    1. Radwan N, Phillips R, Ross A, et al. A phase II randomized trial of observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE) BMC Cancer. 2017;17:453.
    1. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, Rowe SP, Ross AE, Gorin MA, Deville C, Greco SC, Wang H, Denmeade SR, Paller CJ, Dipasquale S, DeWeese TL, Song DY, Wang H, Carducci MA, Pienta KJ, Pomper MG, Dicker AP, Eisenberger MA, Alizadeh AA, Diehn M, Tran PT. 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. PMID: 32215577.
    1. Soldatov A, von Klot CAJ, Walacides D, et al. Patterns of progression after (68) Ga-PSMA-ligand PET/CT-guided radiation therapy for recurrent prostate Cancer. Int J Radiat Oncol Biol Phys. 2019;103:95–104.
    1. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–223.
    1. Deshayes E, Roumiguie M, Thibault C, et al. Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017;11:2643–2651.
    1. Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–594.
    1. Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11:4451–4459.
    1. Hobbs RF, Song H, Watchman CJ, et al. A bone marrow toxicity model for (2)(2)(3) Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57:3207–3222.
    1. Vickers AJ. How to randomize. J Soc Integr Oncol. 2006;4:194–198.
    1. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation counting. Appl Radiat Isot. 2010;68:1523–1528.
    1. Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST standard for (223) Ra: new measurements and review of 2008 data. J Res Natl Inst Stand Technol. 2015;120:37–57.
    1. Xofigo (radium Ra 223 dichloride) Injection [package insert]. Wayne (NJ): Bayer HealthCare Pharmaceuticals Inc. 2013. .
    1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247.
    1. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate Cancer clinical trials working group. J Clin Oncol. 2008;26:1148–1159.
    1. Antonarakis ES, Feng Z, Trock BJ, et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 2012;109:32–39.
    1. Keizman D, Zahurak M, Sinibaldi V, et al. Lenalidomide in nonmetastatic biochemically relapsed prostate cancer: results of a phase I/II double-blinded, randomized study. Clin Cancer Res. 2010;16:5269–5276.
    1. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597.
    1. Kneebone A, Hruby G, Ainsworth H, et al. Stereotactic body radiotherapy for Oligometastatic prostate Cancer detected via prostate-specific membrane antigen positron emission tomography. Eur Urol Oncol. 2018;1:531–537.
    1. Siva S, Bressel M, Murphy DG, et al. Stereotactic Abative body radiotherapy (SABR) for Oligometastatic prostate Cancer: a prospective clinical trial. Eur Urol. 2018;74:455–462.
    1. Moyer CL, Phillips R, Deek MP, et al. Stereotactic ablative radiation therapy for oligometastatic prostate cancer delays time-to-next systemic treatment. World J Urol. 2019;37:2623–2629.
    1. De Bleser E, Tran PT, Ost P. Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. Curr Opin Urol. 2017;27:587–595.
    1. Muldermans JL, Romak LB, Kwon ED, Park SS, Olivier KR. Stereotactic body radiation therapy for Oligometastatic prostate Cancer. Int J Radiat Oncol Biol Phys. 2016;95:696–702.
    1. Ost P, Jereczek-Fossa BA, As NV, et al. Progression-free survival following stereotactic body radiotherapy for Oligometastatic prostate Cancer treatment-naive recurrence: a multi-institutional analysis. Eur Urol. 2016;69:9–12.
    1. Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic body radiotherapy for oligometastatic prostate cancer recurrence. Radiat Oncol. 2014;9:135.
    1. Ahmed KA, Barney BM, Davis BJ, Park SS, Kwon ED, Olivier KR. Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancer. Front Oncol. 2012;2:215.
    1. Loi M, Di Cataldo V, Francolini G, et al. Single-fraction stereotactic body radiotherapy for Oligometastatic lymph node relapse in prostate Cancer. Oncol Res Treat. 2018;41:703–705.
    1. Markowski MC, Imus P, Wright JL, Schottenstein D, Paller CJ. Long-term control of Oligometastatic prostate Cancer after stereotactic body radiotherapy in the absence of androgen deprivation therapy: a case report. Clin Genitourin Cancer. 2017;15:e839–ee42.
    1. Ingrosso G, Trippa F, Maranzano E, et al. Stereotactic body radiotherapy in oligometastatic prostate cancer patients with isolated lymph nodes involvement: a two-institution experience. World J Urol. 2017;35:45–49.
    1. Pasqualetti F, Panichi M, Sainato A, et al. [(18) F] Choline PET/CT and stereotactic body radiotherapy on treatment decision making of oligometastatic prostate cancer patients: preliminary results. Radiat Oncol. 2016;11:9.
    1. Schick U, Jorcano S, Nouet P, et al. Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases. Acta Oncol. 2013;52:1622–1628.
    1. Tosoian JJ, Gorin MA, Ross AE, Pienta KJ, Tran PT, Schaeffer EM. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol. 2017;14:15–25.
    1. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial. BMC Cancer. 2019;19:816.

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