177Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer and Prior 223Ra (RALU Study)

Visual Abstract

Met astatic prostate cancer is largely a disease of the bone (1), with a 5-y survival rate of less than 30% (2).For patients with metastatic castration-resistant prostate cancer (mCRPC), available lifeprolonging therapies include taxane-based chemotherapy (docetaxel and cabazitaxel), androgen receptor pathway inhibitors (abiraterone and enzalutamide), the radionuclide 223 Ra-dichloride ( 223 Ra), the immunologic agent sipuleucel-T, the poly (adenosine diphosphate ribose) polymerase inhibitor olaparib, and 177 Lu-vipivotide tetraxetan, consisting of a radionuclide ( 177 Lu) linked to a ligand that binds to prostate-specific membrane antigen (PSMA), referred to as 177 Lu-PSMA-617 hereafter (3)(4)(5)(6)(7)(8). 223Ra is an a-particle-emitting radionuclide that mimics calcium and is incorporated into newly forming bone surrounding metastatic lesions (9,10).a-particles have high linear energy transfer, and the energy emitted by 223 Ra decay causes DNA double-strand breaks that are difficult to repair (11). 223Ra is approved for the treatment of mCRPC with bone metastases but without visceral involvement (12,13).It is an established therapy that prolongs overall survival (OS) and has a favorable safety profile in this setting, as demonstrated in the phase 3 ALSYMPCA study (14,15).In contrast, 177 Lu-PSMA-617 is a b-particle emitter that targets PSMAexpressing cells.On the basis of results from the phase 3 VISION study (16), 177 Lu-PSMA-617 was recently approved in the United States and Europe for the treatment of PSMA-positive mCRPC in patients who have previously received docetaxel (7,8).In this trial, 177 Lu-PSMA-617 therapy showed an acceptable safety profile and prolonged OS in patients heavily pretreated with other lifeprolonging agents (in addition to docetaxel), including 223 Ra (16).
Because of their differing mechanisms of action, there is considerable interest in understanding how 223 Ra and 177 Lu-PSMA-617 therapy at different time points in the therapeutic sequence may affect safety and efficacy outcomes.Notably, in VISION, patients (17.4%) treated with 177 Lu-PSMA-617 who had previously received 223 Ra therapy had benefits consistent with those of the overall patient population (17), although the safety for these patients has not yet been reported.However, small observational studies using 177 Lu conjugated to various PSMA ligands indicate favorable toxicity and OS benefit in patients previously treated with 223 Ra (18)(19)(20), including when 177 Lu-PSMA therapy was initiated within 8 wk of stopping 223 Ra (21).
Additional studies are required to provide further evidence of the safety and efficacy of sequential 223 Ra and 177 Lu-PSMA therapy.Here, we report findings from the radium!lutetium (RALU) study, which was designed to investigate the safety and efficacy of real-world 177 Lu-PSMA use in patients with mCRPC who had previously received 223 Ra.Additional post hoc analyses investigated whether 177 Lu-PSMA safety or efficacy is impacted by the time between the last 223 Ra dose and the first 177 Lu-PSMA dose or prior use of both taxanes and 223 Ra.

Study Design
RALU is a multicenter, retrospective medical chart review study in Germany.This analysis reports final data from participating university hospitals.The study was conducted in accordance with guidelines and regulations of the European Medicines Agency and applicable local laws and regulations.The study protocol was approved by the institutional review board at each center.The requirement to obtain informed consent was waived because of the retrospective nature of the study and the fact that the patients were deceased or in a terminal disease stage.

Patients
Patients whose medical records were evaluated in this study were not assigned to a particular therapeutic strategy.All treatment decisions documented in the patients' medical records were made solely by the treating physicians in consultation with their patients as part of routine clinical practice.All treatment decisions were made within current clinical practice.Patients were assigned unique central identification codes, and only the treating physician, authorized site personnel, and authorized monitors and auditors had access to uncoded data.
Eligible patients were men aged at least 18 y, with a confirmed diagnosis of mCRPC, who had received at least 1 223 Ra dose and, in any subsequent therapy line, at least 1 177 Lu-PSMA dose.Chemotherapy before 177 Lu-PSMA was allowed but not required.Exclusion criteria included previous treatment with hemibody radiation and radionuclide therapies other than 223 Ra and 177 Lu-PSMA.Patients were selected and their data collected by trained study-site personnel.

Procedures
Medical records were retrospectively reviewed between September 2021 and March 2022 (patients were treated between December 2014 and July 2021).The retrospective observation period started at mCRPC diagnosis and ended at the last available visit or death, whichever occurred first.The study design is shown in Figure 1.The radiation dose, activity, and date of each 223 Ra injection were collected.177 Lu-PSMA therapy with any PSMA-targeted moiety was allowed, and the name or composition of the medicinal product, specification of the PSMA-targeted ligand, and radiation dose or activity and dates for each administration were collected.For chemotherapy exposure (docetaxel and cabazitaxel), the name and composition of the medicinal product, number of therapy cycles, calendar date for first and last administrations, and presence or absence of adverse events (AEs) were recorded.Use of other life-prolonging therapies was also documented (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, and 223 Ra).

Outcomes
The primary objective was to describe the safety of 177 Lu-PSMA therapy in patients previously treated with 223 Ra.Primary endpoints included the incidence of AEs and serious AEs, measured from the start of 177 Lu-PSMA therapy up to 30 d after the last dose, and abnormal laboratory values (graded according to the Common Terminology Criteria for Adverse Events [version 5.0; AEs were graded retrospectively]) and grade 3-4 hematologic toxicities, measured from the start of 177 Lu-PSMA therapy up to 90 d after the last dose.Secondary endpoints were the incidence of grade 3-4 laboratory abnormalities during 177 Lu-PSMA treatment when chemotherapy was given before or after 223 Ra therapy, OS from the start of 177 Lu-PSMA treatment, time to next treatment or death, and changes from baseline in serum prostatespecific antigen (PSA) and alkaline phosphatase (ALP) levels measured during 177 Lu-PSMA therapy.
Additional analyses were conducted for patients who received 177 Lu-PSMA therapy for less than 6 mo versus 6 mo or more after the last 223 Ra dose and for patients who received prior taxane-based chemotherapy in one of the following sequences: taxane-based chemotherapy, then 223 Ra, then 177 Lu-PSMA (Tax!Ra!Lu) or 223 Ra, then taxane-based chemotherapy (during or after 223 Ra), then 177 Lu-PSMA (Ra!Tax!Lu).

Statistical Analysis
Statistical analyses were exploratory; descriptive statistics were used.The study did not aim to confirm or reject predefined hypotheses.Summary statistics for duration of exposure and total number of treatment cycles were generated separately for 177 Lu-PSMA, 223 Ra, and chemotherapy.For OS and time to next treatment or death, median and 95% CIs were estimated using the Kaplan-Meier method.Summary statistics were generated for changes from baseline in ALP and PSA.No data imputation was planned.

Patients
In total, 133 patients with mCRPC were treated with 223 Ra and subsequent 177 Lu-PSMA.The patient disposition is shown in Supplemental Table 1 (supplemental materials are available at http://jnm.snmjournals.org).Baseline demographics and clinical characteristics at the start of 177 Lu-PSMA therapy are provided in Table 1.Patients had an Eastern Cooperative Oncology Group performance status of either 1 (82/133, 62%) or 2 (51/133, 38%).Visceral metastases were present in 36 of 133 (27%) patients, with half of those having liver involvement (18/36, 50%).Median PSA and ALP values were 286 ng/mL and 146 U/L (Table 1).
Lu-PSMA treatment.The incidence of grade 3-4 laboratory abnormalities was similar irrespective of whether patients received 177 Lu-PSMA less than 6 mo or 6 mo or more after their last 223 Ra dose (Table 4).Notably, 25 of 42 (60%) patients received 177 Lu-PSMA within 12 wk after 223 Ra in the less-than-6-mo subgroup.

DISCUSSION
Here we show that 177 Lu-PSMA therapy in patients with mCRPC previously treated with 223 Ra is clinically feasible, with safety and survival outcomes similar to those reported in the VISION trial (16), other smaller studies (19)(20)(21)(22), and a preplanned interim analysis of the current study (23).
Although 223 Ra and 177 Lu-PSMA were associated with a low incidence of myelosuppression in randomized trials (14,16,24), the potential risk of increased hematologic AEs requires consideration when using sequential systemic radionuclide therapies, particularly in the context of chemotherapy exposure and advanced disease (19,25,26).The current study provides important insights into the feasibility of sequencing radiopharmaceuticals.The incidence of Common Terminology Criteria for Adverse Events grade 3-4 anemia and thrombocytopenia (15% and 2%) in RALU was consistent with the results (15% and 4%) of the prospective noninterventional REASSURE study in patients who received 177 Lu-PSMA subsequent to 223 Ra (22) and the results (13% and 8%) of the 177 Lu-PSMA-617 arm of the prospective interventional VISION trial (16).These findings suggest that using 223 Ra and 177 Lu-PSMA sequentially is not associated with cumulative hematologic toxicity.
Our results show that the safety profile and OS outcomes of 177 Lu-PSMA were similar whether taxanes were used before or after 223 Ra.Furthermore, 59% of patients received 223 Ra early in the treatment sequence (first or second line after mCRPC diagnosis).Thus, receiving 223 Ra earlier in the treatment sequence did not prevent these patients from receiving subsequent cytotoxic therapies such as taxanes or 177 Lu-PSMA.Further studies on the optimal use of available therapies are warranted, including combined (27) or alternating use of 223 Ra and 177 Lu-PSMA (given their complementary mechanisms of action).
These data provide physicians with important information regarding the hematologic safety of receiving 2 systemic radiopharmaceuticals.Because physicians with different medical specialties or disciplines manage patients at this advanced stage, interaction and communication within a multidisciplinary medical team (including radiologists, nuclear medicine physicians, radiology nurses, oncologists, and urologists) is important to ensure that patients are receiving the best available care.This was conveyed in an expert recommendation paper from nuclear medicine centers across Europe, in which guidance on optimizing 223 Ra use was delineated and outlined (28).
Our findings require consideration of the study limitations, among which are its retrospective design (potentially contributing to patient selection bias), lack of a control arm, and data that are from a single country.However, our study is strengthened by its relatively unconstrained inclusion criteria, the fact that there are few missing data, and the fact that patients were treated in nuclear medicine centers with extensive experience with 223 Ra and 177 Lu-PSMA.

CONCLUSION
In this real-world setting of patients with mCRPC previously treated with 223 Ra, 177 Lu-PSMA therapy had an acceptable safety profile and effectiveness comparable to that seen in the VISION trial.These data also support the feasibility of giving 177 Lu-PSMA within 6 mo of completing 223 Ra therapy.Furthermore, safety and OS outcomes were similar regardless of the order of chemotherapy use in the sequence (e.g., before or after 223 Ra).These findings may inform decision making when considering treatment strategies for patients with mCRPC and bone metastases, with the ultimate goal of prolonging life using the right treatment at the right time.

KEY POINTS
QUESTION: Can 177 Lu-PSMA be safely given to patients with mCRPC if they have previously received 223 Ra, and is safety impacted depending on where 223 Ra is positioned in the treatment sequence?
PERTINENT FINDINGS: In this real-world setting, 177 Lu-PSMA had an acceptable safety profile in patients who had previously received 223 Ra, with low rates of hematologic and overall AEs.Median OS from the first dose of 177 Lu-PSMA was 13.2 mo and was similar irrespective of whether patients had received taxane-based chemotherapy before or after 223 Ra or if the time between 223 Ra and 177 Lu-PSMA was less than 6 mo versus 6 mo or more.

IMPLICATIONS FOR PATIENT CARE:
In patients with mCRPC and prior 223 Ra therapy, 177 Lu-PSMA had an acceptable safety profile and an effectiveness comparable to that seen in the VISION trial, irrespective of when patients had received prior 223 Ra.

Treatment Diagnosis Follow-up Inclusion criteria
: • Confirmed mCRPC diagnosis • Patients have received ≥1 dose of 223 Ra • Patients have received ≥1 dose of 177 Lu-PSMA (started at a later time after completion of 223 Ra)

From mCRPC diagnosis to 60 days prior to start of 177 Lu-PSMA
FIGURE 1. RALU study design.*Data also collected during 177 Lu-PSMA therapy and during followup period after last 177 Lu-PSMA dose.† Measured from start of 177 Lu-PSMA therapy up to 30 d after last dose.‡ Measured from start of 177 Lu-PSMA therapy up to 90 d after last dose.§ Measured from both start of 223 Ra and start of 177 Lu-PSMA.|| Measured from start of 177 Lu-PSMA.¶ Measured during 60-d baseline period and during follow-up.SAE 5 serious AE.

TABLE 1
Baseline Demographics and Clinical Characteristics Before or at Start of 177 Lu-PSMA † Prebaseline period, patient may have multiple metastatic diseases.‡ Docetaxel, cabazitaxel, abiraterone, enzalutamide, 223 Ra. § Chemotherapies with same start date 6 15 d were counted as Safety and Efficacy of 177 Lu-PSMA When Both223Ra and Chemotherapy Were Prior Therapies Analyses were conducted on patients who had received both taxane-based chemotherapy and 223 Ra before 177 Lu-PSMA.Patients were grouped depending on whether they had received taxane-based chemotherapy during or after223Ra treatment (Ra!Tax!Lu; n 5 57) or before (Tax!Ra!Lu; n 5 50).Baseline characteristics of these subgroups are reported in Supplemental Table 4.Of the 57 patients who received taxane-based chemotherapy during or after Qualitative data are number and percentage; continuous data are median and range.Patients switched to another carrier molecule are reported under first carrier molecule.
† Patients could have .1 delay and .1 reason for different delays.

TABLE 3
TEAEs During 177 Lu-PSMA Therapy Time between end of 223 Ra and start of 177 Lu-PSMA* *Time between therapies was unknown in 1 patient and therefore not included in this analysis.† Categories selected by incidence of TEAEs in any group.Excludes laboratory abnormalities.CTCAE 5 Common Terminology Criteria for Adverse Events; MedDRA 5 Medical Dictionary for Regulatory Activities; PT 5 preferred term.Data are from start of 177 Lu-PSMA treatment to 30 d after last dose.MedDRA PT is by CTCAE grading.

TABLE 4
Incidence of Grade 3-4 Laboratory Abnormalities During 177 Lu-PSMA Therapy Eight of 17 patients had thrombocytopenia at start of 177 Lu-PSMA.ASAT 5 aspartate aminotransferase.Data are from start of 177 Lu-PSMA treatment to 90 d after last dose. †

From first dose of 223 Ra B
Kaplan-Meier estimates of OS from first dose of 177 Lu-PSMA (A) and first dose of 223 Ra (B).Descriptive statistics and Kaplan-Meier survival probabilities were generated.