Maarten van der Doelen

Chapter 8

The majority of patients (67%) had a fracture in the treatment period while still being treated with abiraterone, after the concurrent use of radium-223. Remarkably, most patients (79%) had no bone metastasis at the site of the fracture. (104) Subgroup analyses of the radium-223 armrevealed that the incidence of symptomatic pathological fractures was significantly higher in patients who did not use concurrent bone health agents (i.e. bisphosphonates or denosumab) (15% versus 1%). (106) Moreover, no OS benefit was found for the radium-223 arm. (104) The ERA 223 outcomes led to revised prescribing recommendations by the EMA, advising radium-223 only to be used in patients with symptomatic bone mCRPC, without (history of ) visceral metastases, having progressive disease after at least two prior lines of systemic treatment. Because the use of radium-223 tends to be associated with an increased risk of fracture during and after treatment, the concurrent use of bone health agents was recommended, as these agents strongly reduce the incidence of fractures. The safety and tolerability of radium-223 in combination with enzalutamide have been evaluated in three recent phase 2 trials, including one randomized trial. (107-110) Results revealed safety profiles consistent with known safety profiles of the individual agents. The combination resulted in a higher incidence of leukopenia, neutropenia, diarrhea and fatigue when compared to the enzalutamide monotherapy arm. (107) However, grade 3-4 adverse events were similar in both treatment arms. Combination treatment did not increase the incidence of skeletal-related events. (108) Furthermore, serum bone metabolism markers decreased significantly more in the combination arm when compared to the enzalutamide monotherapy arm. (107) The combination of docetaxel chemotherapy and radium-223 was recently investigated in a phase 1/2a clinical trial. (111) Radium-223 (55 kBq/kg every six weeks, maximally 5 doses) plus docetaxel (60mg/m 2 every three weeks, maximally 10 cycles) was well tolerated, with even less adverse events than in the docetaxel monotherapy arm. Furthermore, patients who received the combination of therapies had longer times to ALP and PSA progression and greater declines in biomarkers of osteoblastic activity. (111) The efficacy of the combination of radium-223 with docetaxel, enzalutamide and PARP inhibitors niraparib and olaparib will be assessed in ongoing prospective randomized phase 3 clinical trials (DORA, PEACE-3, NiraRad and COMRADE trials, respectively). Subgroup analyses should be carried out to select the best candidates for each combinatory agent.

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