Safety and Survival Outcomes of 177Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer with Prior 223Ra treatment: The RALU Study

Visual Abstract

Over all survival and quality of life in patients with bonepredominant metastatic castration-resistant prostate cancer (mCRPC) was improved by 223 Ra-dichloride, a targeted a-therapy with a good safety profile (1). 223 Ra therapy results in low myelosuppression rates, and recent preclinical data demonstrated its transient effect on the bone marrow without long-term effects (1,2). Therefore, earlier incorporation of 223 Ra in the treatment sequence may facilitate optimal build-in of life-prolonging therapies to improve survival outcomes.
The VISION study investigated a b-emitter, 177 Lu-PSMA-617, targeting PSMA-expressing cells and found prolonged overall survival and acceptable safety in heavily pretreated patients with mCRPC (3). Another 177 Lu-PSMA radioligand ( 177 Lu-PSMA-I&T) was also well tolerated, with few hematologic adverse events (AEs) of grade 3 or higher (4). 223 Ra and 177 Lu-PSMA regulatory approval (in some countries) for patients with mCRPC, albeit in different patient populations, prompted us to investigate the safety and survival outcomes of sequential 223 Ra and 177 Lu-PSMA. In VISION, 17.4% of patients received 223 Ra therapy before 177 Lu-PSMA without adversely affecting efficacy, but safety has not been reported for this subgroup (5). However, retrospective studies have shown that using 223 Ra before 177 Lu-PSMA is feasible, with acceptable safety (6,7). Moreover, 177 Lu-PSMA-617 initiation at no more than 8 wk after 223 Ra in patients with progressive bone-metastatic disease was effective, with acceptable safety (8). We analyzed interim data from the observational radium lutetium (RALU) study to further evaluate safety and survival for sequential 223 Ra and 177 Lu-PSMA therapy in patients with mCRPC.

MATERIALS AND METHODS
The RALU study was a retrospective, multicenter medical chart review investigating the safety of 177 Lu-PSMA in patients with mCRPC previously treated with 223 Ra. This analysis includes patients treated in Germany. Patients were at least 18 y old with mCRPC and received at least 1 223 Ra injection and subsequently at least 1 177 Lu-PSMA cycle.
The retrospective observation period started at mCRPC diagnosis and ended either at the last available visit or death, whichever occurred first. Prebaseline, baseline, and follow-up period definitions are shown in Figure 1.
The primary endpoint was the safety of 177 Lu-PSMA after 223 Ra therapy. AEs used Common Terminology Criteria for Adverse Events grading. Secondary endpoints included OS, time to next treatment, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. AEs and grade 3-4 laboratory abnormalities were recorded as per Figure 1.
The study was conducted in accordance with relevant guidelines and regulations (supplemental methods).

DISCUSSION
Randomized trials have demonstrated low myelosuppression rates in patients with mCRPC receiving 223 Ra or 177 Lu-PSMA (1,3,9). However, chemotherapy and advanced disease affecting bone marrow function can increase myelosuppression rates in this setting (10)(11)(12). Therefore, in real-world practice, radiopharmaceutical therapy after prior chemotherapy may result in more serious hematologic AEs. 177 Lu-PSMA after 223 Ra treatment had an acceptable safety profile. Notably, this was despite the heavy pretreatment of the patient population, with more than 90% of patients having received chemotherapy in addition to 223 Ra and 177 Lu-PSMA. Grade 3-4 anemia and thrombocytopenia incidences were 18% and 2%, respectively, consistent with the retrospective analysis of patients receiving the 223 Ra and 177 Lu-PSMA sequence in the real-world REASSURE study (15% and 4%, respectively) (6). When 177 Lu-PSMA was given within 8 wk of 223 Ra, the incidence of anemia of at least grade 3 was similar (18%), but the rates of leukopenia and thrombocytopenia of at least grade 3 were higher than reported here (14% vs. 0 and 21% vs. 2%, respectively) (8).
The median overall survival from the start of 177 Lu-PSMA or 223 Ra therapy (12.6 and 31.4 mo, respectively) corresponded to that reported in REASSURE (13.2 and 28.0 mo, respectively) (6). In patients with mCRPC who underwent 177 Lu-PSMA therapy in the WARMTH study, overall survival was longer in patients with bone metastases receiving prior 223 Ra than in those who did not (16 vs. 12 mo in patients with 6-20 bone lesions, P 5 0.038, and 11 vs. 7 mo in patients with diffuse involvement, P 5 0.034) (12).
This study's strength is underlined by broad inclusion criteria and high-quality data with few missing datapoints. Accordingly, we could effectively evaluate 177 Lu-PSMA safety in patients with a history of 223 Ra therapy who received chemotherapy, before or after 223 Ra treatment. Nevertheless, a retrospective study design may have contributed to a patient selection bias due to the preset  *Four of 6 had low platelets at baseline, with further reductions at follow-up (1 had chemotherapy before 177 Lu-PSMA); 1 of 6 had normal platelets at baseline, with reductions seen after chemotherapy and at follow-up; 1 of 6 had normal platelets at baseline, with reduction at follow-up. outcomes of interest. Other limitations include retrospective AE grading, lack of ascertainment of 177 Lu-PSMA doses and schedules, and a lack of comparison to patients who were not pretreated with 223 Ra. Despite small patient numbers, patients were managed and treated in high-volume German nuclear medicine centers with extensive 223 Ra and 177 Lu-PSMA experience.

CONCLUSION
This retrospective cohort study demonstrated that, for patients with bone-predominant mCRPC who were receiving 223 Ra in routine care, subsequent 177 Lu-PSMA treatment was clinically feasible and well tolerated, with limited myelosuppression. Survival outcomes reflected those of previous reports. Therefore, in patients with bone-predominant mCRPC, 223 Ra use before 177 Lu-PSMA can be considered in future assessments of the optimal sequence for life-prolonging therapies.

DISCLOSURE
Cancer Communications and Consultancy Ltd., Cheshire, U.K., provided medical writing assistance (funded by Bayer). Dr. Lila Adnane (Bayer) provided editorial assistance. Kambiz Rahbar receives honoraria from Advanced Accelerator Applications (AAA) and Bayer and has a consultancy/ advisory role with ABX GmbH, ABX-CRO, Bayer, and AAA. Markus Essler has a consultancy/advisory role with Bayer, AAA, and Ipsen and receives travel funds from Ipsen.

KEY POINTS
QUESTION: Is it safe to use 177 Lu-PSMA to treat patients with mCRPC if they have previously received 223 Ra?
PERTINENT FINDINGS: Low rates of overall and hematologic AEs indicated an acceptable safety profile for this treatment sequence. Median OS was 12.6 and 31.4 mo from the first dose of 177 Lu-PSMA and 223 Ra, respectively, and 39% of patients had at least a 30% decline in prostate-specific antigen.
IMPLICATIONS FOR PATIENT CARE: Introduction of 223 Ra early in the treatment sequence in patients with bone-predominant mCRPC and subsequent treatment with 177 Lu-PSMA is feasible, well tolerated, and effective.