177Lu-Prostate-Specific Membrane Antigen Ligand After 223Ra Treatment in Men with Bone-Metastatic Castration-Resistant Prostate Cancer: Real-World Clinical Experience

Visual Abstract

The a-emitter 223 Ra demonstrated significantly prolonged overall survival and a favorable safety profile versus placebo in men with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial (1). 177 Lu-prostate-specific membrane antigen ligand ( 177 Lu-PSMA) is an investigational b-emitting radioligand with accumulating evidence of clinical efficacy and acceptable toxicity in men with advanced-stage mCRPC (2)(3)(4)(5).
Early experience in patients who have received both 223 Ra and 177 Lu-PSMA indicates tolerable safety and therapeutic response with this sequence (6)(7)(8). We sought to add to the evidence base on sequential a-/b-emitting therapy, using data from participants in an ongoing global, prospective, observational study of 223 Ra who received subsequent 177 Lu-PSMA.

MATERIALS AND METHODS
Patients with mCRPC involving bone and who were scheduled to receive 223 Ra in clinical practice were included in REASSURE ( 223 Ra a-Emitter Agent in Nonintervention Safety Study in mCRPC Population for Long-Term Evaluation; NCT02141438). Primary outcomes included short-term and long-term safety. Methods and results from a previous interim analysis have been reported (9). This paper is based on the second prespecified interim analysis (data cutoff, March 20, 2019).
Disease characteristics, adverse events after 223 Ra treatment, and overall survival are described for patients who received the experimental drug 177 Lu-PSMA in compassionate-use or investigational settings after 223 Ra. Treatment-emergent serious adverse events and drug-related adverse events were recorded during 223 Ra treatment or up to 30 d after the last 223 Ra dose. Grade 3 or 4 hematologic adverse events were systematically collected up to 6 mo after 223 Ra; neutropenic fever or hemorrhage were recorded in patients with subsequent chemotherapy up to 6 mo after the last dose of chemotherapy. Drugrelated serious adverse events continued to be recorded until the end of follow-up (maximum, 7 y). Adverse events during and after 177 Lu-PSMA therapy were not systematically recorded unless they met the above criteria.
The study conduct complied with the requirements of the European Medicines Agency, the U.S. Food and Drug Administration, applicable local laws and regulations, and International Conference on Harmonization good-clinical-practice guidance. Participants provided written informed consent, and ethics committee or institutional review board approvals were obtained according to local laws in participating countries.

DISCUSSION
Although 177 Lu-PSMA is not yet approved for patients with mCRPC, patients are increasingly receiving this investigational treatment in clinical trials or compassionate-use programs.
Most patients receive 177 Lu-PSMA after multiple prior systemic anticancer therapies, including 223 Ra in some cases, as recorded in the REASSURE study. This subgroup analysis of REASSURE, which reflects real-world clinical practice, adds to the evidence for the feasibility of sequential 223 Ra and 177 Lu-PSMA treatment, with a median overall survival of more than 1 y from the start of 177 Lu-PSMA therapy. Only 3 patients had serious adverse events related to 223 Ra, and the reported (albeit incompletely) incidence of grade 3 hematologic events was acceptable, mostly consisting of anemia, which may be partially explained by increasing disease burden. Furthermore, the treatment duration for 177 Lu-PSMA (median, 3.5 mo) indicates that several patients were able to receive multiple cycles, even though most patients had received at least 3 prior life-prolonging therapies, including taxane chemotherapy.
The 13-mo median overall survival in our analysis is consistent with a retrospective multicenter study in which median overall survival from the start of 177 Lu-PSMA therapy was around 11 mo in 85 patients with prior 223 Ra (7) and 16.4 mo in patients with 6-20 bone lesions treated with 223 Ra and 177 Lu-PSMA (10). In another analysis, rates of grade 3 hematologic toxicity were low in patients with or without prior 223 (6), a result that again supports our findings, although we did not systematically assess hematologic toxicity in all patients during 177 Lu-PSMA treatment-a limitation of our study.
Additional limitations are the small sample size, reflecting the experimental status of 177 Lu-PSMA, and the lack of a randomized control group. Because 177 Lu-PSMA is still an investigational agent, treatment was likely undertaken in academic settings (e.g., university hospital cancer centers); it is therefore unknown whether the findings can be extrapolated to real-world community settings.  The treatment duration and overall survival after 177 Lu-PSMA initiation indicate that its use after 223 Ra in heavily pretreated mCRPC patients is feasible, but interpretation is hindered by lack of a comparator arm, and possibly only the fittest patients were selected for 177 Lu-PSMA treatment. Nevertheless, this interim analysis of an ongoing real-world study provides clinically meaningful evidence in patients with mCRPC who successfully received sequential a-/b-emitting treatments. PERTINENT FINDINGS: Subgroup analysis of a global observational study of 223 Ra therapy indicated a low rate of serious adverse events and hematologic toxicities in patients who also received 177 Lu-PSMA, and many patients were able to receive multiple doses of 177 Lu-PSMA (a marker of tolerability). This sequence provides overall survival of more than 2 y from the initiation of 223 Ra and more than 1 y from the initiation of 177 Lu-PMSA, even in heavily pretreated patients.
IMPLICATIONS FOR PATIENT CARE: Sequential use of aand b-emitters appears to be feasible in selected patients, on the basis of the known safety profile of 223 Ra and the duration of subsequent 177 Lu-PSMA; this sequence warrants further investigation. *No grade $4 events were recorded. † Patients may have had .1 event at different times; these patients are counted only once in "Any" row and "Overall" column. ‡ Grade 3/4 hematologic toxicity data were systematically recorded only up to 6 mo after completion of 223 Ra therapy; data are therefore not consistently available for patients who received 177 Lu-PSMA after this window.
Qualitative data are number and percentage.