Maarten van der Doelen

General discussion and future perspectives

99) However, relapses after MDT occur frequently, and mostly in the bone, probably because a significant proportion of patients has subclinical micrometastatic disease in the bone. (100) The addition of radium-223 to SABR as multimodality treatment to treat both macrometastatic and micrometastatic disease might improve outcomes of MDT and postpone ADT or other systemic treatments. Currently, the phase 2, non-blinded, randomized RAVENS trial is investigating the additive role of radium-223 to SABR for patients with mHSPC and oligometastases to the bone. (101) Radium-223 re-treatment In a prospective phase 1/2 study, 44 patients with progressive disease after six initial cycles were re-treated with radium-223. The included patients had shown no on treatment bone progression during initial radium-223 treatment. (102) Re-treatment was well tolerated with minimal hematological toxicity and no major adverse events during two years of active follow-up. (103) Median OS was 24.4 months in this selected patient population. Sixty-six percent of patients received all six re-treatment injections. Soft tissue disease progression occurred in eight (18%) patients. (102) Based on these study outcomes, re-treatment with radium-223 seems effective in selected patients. However, factors for the identification of these patients have not been described. Patients with bone-only disease, good performance status and ALP and PSA response during the first six radium-223 injections are probably the best candidates for successful re-treatment. Combining targeted alpha-radionuclide therapies with other agents Combining TAT with other approved anti-prostate cancer therapies, acting through different mechanisms of action, may synergize on effectiveness while maintaining manageable toxicity. Based on this rationale, numerous trials have started investigating radium-223 in combination with other life-prolonging agents, including abiraterone, docetaxel, enzalutamide, PARP inhibitors and sipuleucel-T. (31) Combining radium-223 with other agents The double-blind, randomized phase 3 ERA 223 trial has investigated radium-223 in combination with abiraterone (radium-223 arm) versus placebo in combination with abiraterone (placebo arm) in asymptomatic or mildly symptomatic patients with chemotherapy-naïve bone mCRPC. (104) By the end of 2017 preliminary results of the ongoing trial resulted in a warning for the concomitant use of abiraterone with radium-223 by the European Medicines Agency (EMA). (105) The combination of radium-223 plus abiraterone appeared to result in a higher incidence of treatment emergent fractures when compared to the placebo arm (29% versus 11%, respectively).

8

213