Visual Abstract
Abstract
223Ra-dichloride (223Ra) and 177Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223Ra and 177Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223Ra. Methods: The radium→lutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223Ra dose and, in any subsequent therapy line, at least 1 177Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3–4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223Ra (73% received 5–6 injections). Overall, 27% (36/133) of patients received at least 5 177Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3–4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5–15.6 mo) from the start of 177Lu-PSMA. Conclusion: In this real-world setting, 223Ra followed by 177Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177Lu-PSMA safety or effectiveness.
Metastatic 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 life-prolonging therapies include taxane-based chemotherapy (docetaxel and cabazitaxel), androgen receptor pathway inhibitors (abiraterone and enzalutamide), the radionuclide 223Ra-dichloride (223Ra), the immunologic agent sipuleucel-T, the poly (adenosine diphosphate ribose) polymerase inhibitor olaparib, and 177Lu-vipivotide tetraxetan, consisting of a radionuclide (177Lu) linked to a ligand that binds to prostate-specific membrane antigen (PSMA), referred to as 177Lu-PSMA-617 hereafter (3–8).
223Ra is an α-particle–emitting radionuclide that mimics calcium and is incorporated into newly forming bone surrounding metastatic lesions (9,10). α-particles have high linear energy transfer, and the energy emitted by 223Ra 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, 177Lu-PSMA-617 is a β-particle emitter that targets PSMA-expressing cells. On the basis of results from the phase 3 VISION study (16), 177Lu-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, 177Lu-PSMA-617 therapy showed an acceptable safety profile and prolonged OS in patients heavily pretreated with other life-prolonging agents (in addition to docetaxel), including 223Ra (16).
Because of their differing mechanisms of action, there is considerable interest in understanding how 223Ra and 177Lu-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 177Lu-PSMA-617 who had previously received 223Ra 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 177Lu conjugated to various PSMA ligands indicate favorable toxicity and OS benefit in patients previously treated with 223Ra (18–20), including when 177Lu-PSMA therapy was initiated within 8 wk of stopping 223Ra (21).
Additional studies are required to provide further evidence of the safety and efficacy of sequential 223Ra and 177Lu-PSMA therapy. Here, we report findings from the radium→lutetium (RALU) study, which was designed to investigate the safety and efficacy of real-world 177Lu-PSMA use in patients with mCRPC who had previously received 223Ra. Additional post hoc analyses investigated whether 177Lu-PSMA safety or efficacy is impacted by the time between the last 223Ra dose and the first 177Lu-PSMA dose or prior use of both taxanes and 223Ra.
MATERIALS AND METHODS
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 223Ra dose and, in any subsequent therapy line, at least 1 177Lu-PSMA dose. Chemotherapy before 177Lu-PSMA was allowed but not required. Exclusion criteria included previous treatment with hemibody radiation and radionuclide therapies other than 223Ra and 177Lu-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 223Ra injection were collected. 177Lu-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 223Ra).
RALU study design. *Data also collected during 177Lu-PSMA therapy and during follow-up period after last 177Lu-PSMA dose. †Measured from start of 177Lu-PSMA therapy up to 30 d after last dose. ‡Measured from start of 177Lu-PSMA therapy up to 90 d after last dose. §Measured from both start of 223Ra and start of 177Lu-PSMA. ‖Measured from start of 177Lu-PSMA. ¶Measured during 60-d baseline period and during follow-up. SAE = serious AE.
Outcomes
The primary objective was to describe the safety of 177Lu-PSMA therapy in patients previously treated with 223Ra. Primary endpoints included the incidence of AEs and serious AEs, measured from the start of 177Lu-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 177Lu-PSMA therapy up to 90 d after the last dose. Secondary endpoints were the incidence of grade 3–4 laboratory abnormalities during 177Lu-PSMA treatment when chemotherapy was given before or after 223Ra therapy, OS from the start of 177Lu-PSMA treatment, time to next treatment or death, and changes from baseline in serum prostate-specific antigen (PSA) and alkaline phosphatase (ALP) levels measured during 177Lu-PSMA therapy.
Additional analyses were conducted for patients who received 177Lu-PSMA therapy for less than 6 mo versus 6 mo or more after the last 223Ra dose and for patients who received prior taxane-based chemotherapy in one of the following sequences: taxane-based chemotherapy, then 223Ra, then 177Lu-PSMA (Tax→Ra→Lu) or 223Ra, then taxane-based chemotherapy (during or after 223Ra), then 177Lu-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 177Lu-PSMA, 223Ra, 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.
RESULTS
Patients
In total, 133 patients with mCRPC were treated with 223Ra and subsequent 177Lu-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 177Lu-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).
Baseline Demographics and Clinical Characteristics Before or at Start of 177Lu-PSMA
Overall, 75 of 133 (56%) patients had received at least 4 life-prolonging therapies before starting 177Lu-PSMA (Table 1). All patients had received prior 223Ra; 98 (73%) had completed 5–6 injections (Table 1). Abiraterone and enzalutamide had been used to treat 95 (71%) and 92 (69%) patients, respectively; 71 (53%) patients had received both. In total, 102 (77%) patients had received at least 1 taxane-based chemotherapy (Table 1). The precise treatment sequence is known for 114 patients; 223Ra was the first therapy received during mCRPC for 23 of these 114 (20%) patients, second for 45 (40%), and third for 24 (21%) (Supplemental Fig. 1).
The median time from mCRPC diagnosis to the first 177Lu-PSMA dose was 37.8 mo (range, 7.4–161.5 mo), the median time from the last 223Ra injection to the first 177Lu-PSMA dose was 12.0 mo (range, 0.7–74.3 mo), and the median duration of 177Lu-PSMA therapy was 4.4 mo (range, 0.0–57.1 mo) (Table 2). Overall, 97 of 133 (73%) patients received 1–4 177Lu-PSMA infusions and 36 (27%) received at least 5 infusions (Table 2); the median number of infusions was 4. After 177Lu-PSMA therapy, 76 (57%) patients died without receiving further treatment and 20 (15%) subsequently received further life-prolonging therapy (most commonly enzalutamide and abiraterone; no patients received 223Ra or 177Lu-PSMA). Among the subsequent treatment recipients, the median time to the next treatment was 1.1 mo (range, 0.0–2.8 mo). The median time to the next therapy or death from the start of 177Lu-PSMA therapy was 10.9 mo (95% CI, 9.1–13.2 mo), with 15 (11%) patients progressing to the next therapy or death within 30 d of the last 177Lu-PSMA dose.
177Lu-PSMA Therapy
Safety
During 177Lu-PSMA treatment and up to 30 d after the last dose, any-grade treatment-emergent AEs (TEAEs) occurred in 105 of 133 (79%) patients and serious TEAEs in 40 (30%); grade 3–4 and grade 5 TEAEs occurred in 37 (28%) and 5 (4%) patients, respectively (Table 3). In patients who received 177Lu-PSMA within 6 mo versus 6 mo or more after completing 223Ra, any-grade TEAEs were reported in 30 of 42 (71%) versus 74 of 90 (82%) patients, respectively; corresponding values for serious TEAEs were 14 of 42 (33%) versus 25 of 90 (28%) (Table 3). Overall, anemia was the most common grade 3–4 TEAE (20/133, 15%; Supplemental Table 2) and serious TEAE (16/133, 12%; Supplemental Table 3); 2 of 133 (2%) patients had grade 3–4 thrombocytopenia (Supplemental Table 2). One patient (1%) experienced a pathologic fracture (grade 1–2).
TEAEs During 177Lu-PSMA Therapy
The most common grade 3–4 laboratory abnormalities were anemia (40/133; 30%) and thrombocytopenia (17/133, 13%) (Table 4). Of the patients with grade 3–4 thrombocytopenia, 8 of 17 (47%) had preexisting thrombocytopenia before receiving 177Lu-PSMA treatment. The incidence of grade 3–4 laboratory abnormalities was similar irrespective of whether patients received 177Lu-PSMA less than 6 mo or 6 mo or more after their last 223Ra dose (Table 4). Notably, 25 of 42 (60%) patients received 177Lu-PSMA within 12 wk after 223Ra in the less-than-6-mo subgroup.
Incidence of Grade 3–4 Laboratory Abnormalities During 177Lu-PSMA Therapy
Efficacy
Median OS calculated from the first 177Lu-PSMA dose was 13.2 mo (95% CI, 10.5–15.6 mo) (Fig. 2A); OS was similar irrespective of whether patients received 177Lu-PSMA less than 6 mo (12.0 mo [95% CI, 8.8–19.9 mo]) or 6 mo or more (13.2 mo [95% CI, 10.0–15.9 mo]) after their last 223Ra dose (Fig. 3A). When calculated from the first 223Ra dose, median OS was 33.4 mo (95% CI, 31.2–37.4 mo) (Fig. 2B).
Kaplan–Meier estimates of OS from first dose of 177Lu-PSMA (A) and first dose of 223Ra (B). Descriptive statistics and Kaplan–Meier survival probabilities were generated.
Kaplan–Meier estimates of OS by time between end of 223Ra and start of 177Lu-PSMA (A) and from first dose of 177Lu-PSMA by treatment sequence (B). Descriptive statistics and Kaplan–Meier survival probabilities were generated. OS was calculated from first dose of 177Lu-PSMA. For treatment sequence analysis, 13 patients with multiple taxane-based chemotherapy treatments administered before and after 223Ra were included in both groups; patients who did not receive taxane-based chemotherapy (31/133, 23%) were excluded.
Overall, 55 of 133 (41%) patients had available PSA data during 177Lu-PSMA treatment; a PSA decline of at least 30% or at least 50% occurred in 26 (47%) and 23 (42%) patients, respectively. Corresponding ALP declines occurred in 9 (19%) and 4 (9%) of 47 patients.
Safety and Efficacy of 177Lu-PSMA When Both 223Ra and Chemotherapy Were Prior Therapies
Analyses were conducted on patients who had received both taxane-based chemotherapy and 223Ra before 177Lu-PSMA. Patients were grouped depending on whether they had received taxane-based chemotherapy during or after 223Ra treatment (Ra→Tax→Lu; n = 57) or before (Tax→Ra→Lu; n = 50). Baseline characteristics of these subgroups are reported in Supplemental Table 4. Of the 57 patients who received taxane-based chemotherapy during or after 223Ra treatment, 6 patients started chemotherapy during 223Ra therapy and 51 started chemotherapy after 223Ra therapy. Any-grade and grade 3–4 TEAEs occurred in 50 of 57 (88%) and 14 of 57 (25%) patients in the Ra→Tax→Lu group and in 39 of 50 (78%) and 17 of 50 (34%) patients in the Tax→Ra→Lu group, respectively (Supplemental Table 5). A lower proportion of patients had grade 3–4 laboratory abnormalities of anemia and thrombocytopenia in the Ra→Tax→Lu group (15/57 [26%] and 7/57 [12%], respectively) than in the Tax→Ra→Lu group (19/50 [38%] and 9/50 [18%], respectively; Supplemental Table 6). Median OS from the first 177Lu-PSMA dose was 12.0 mo (95% CI, 8.8–14.6 mo) in the Ra→Tax→Lu group and 14.0 mo (95% CI, 9.4–16.9 mo) in the Tax→Ra→Lu group (Fig. 3B).
DISCUSSION
Here we show that 177Lu-PSMA therapy in patients with mCRPC previously treated with 223Ra is clinically feasible, with safety and survival outcomes similar to those reported in the VISION trial (16), other smaller studies (19–22), and a preplanned interim analysis of the current study (23).
Although 223Ra and 177Lu-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 177Lu-PSMA subsequent to 223Ra (22) and the results (13% and 8%) of the 177Lu-PSMA-617 arm of the prospective interventional VISION trial (16). These findings suggest that using 223Ra and 177Lu-PSMA sequentially is not associated with cumulative hematologic toxicity.
Our results show that the safety profile and OS outcomes of 177Lu-PSMA were similar whether taxanes were used before or after 223Ra. Furthermore, 59% of patients received 223Ra early in the treatment sequence (first or second line after mCRPC diagnosis). Thus, receiving 223Ra earlier in the treatment sequence did not prevent these patients from receiving subsequent cytotoxic therapies such as taxanes or 177Lu-PSMA. Further studies on the optimal use of available therapies are warranted, including combined (27) or alternating use of 223Ra and 177Lu-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 223Ra 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 223Ra and 177Lu-PSMA.
CONCLUSION
In this real-world setting of patients with mCRPC previously treated with 223Ra, 177Lu-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 177Lu-PSMA within 6 mo of completing 223Ra therapy. Furthermore, safety and OS outcomes were similar regardless of the order of chemotherapy use in the sequence (e.g., before or after 223Ra). 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.
DISCLOSURE
This work was supported by Bayer AG. Kambiz Rahbar reports honoraria from Advanced Accelerator Applications (AAA) and Bayer and a consultancy/advisory role with ABX GmbH, ABX-CRO, Bayer, and AAA. Markus Essler reports a consultancy/advisory role with Bayer, AAA, and Ipsen and travel expenses from Ipsen. Matthias Eiber reports stocks/other ownership interests in Novartis and Telix Pharmaceuticals; a consultancy/advisory role with Blue Earth Diagnostics, ABX Advanced Biochemical Compounds, Janssen Oncology, Telix Pharmaceuticals, and Novartis; research funding from Siemens, ABX Advanced Biochemical Compounds, Blue Earth Diagnostics, and Bayer; a patent application for rhPSMA; and travel expenses from Bayer Schering Pharma. Christian la Fougère reports a consultancy/advisory role with Bayer, Novartis, EUSA-Pharma, Ipsen, Oncodesign, and Sirtex Medical and research funding from Oncovision and Siemens Healthineers. Vikas Prasad reports honoraria from AAA, a consultancy/advisory role with Bayer, and research funding from Ipsen. Wolfgang Fendler reports honoraria from Parexel and AAA; a consultancy/advisory role with Janssen, Calyx, and Bayer; and research funding from SOFIE. Philipp Rassek is an employee of Porterhouse Group AG Paracelsus Kliniken. Helmut Dittmann reports a consultancy/advisory role with Bayer, Ipsen, and Eisai AG. Ralph Bundschuh reports honoraria from Eisai AG and a consultancy/advisory role with Bayer. Kim Pabst has received a Junior Clinician Scientist Stipend of the University Medicine Essen Clinician Scientist Academy (sponsor: Faculty of Medicine and Deutsche Forschungsgemeinschaft), research funding from Bayer, and travel fees from Ipsen. Milena Kurtinecz, Anja Schmall, and Frank Verholen are employees of Bayer. Oliver Sartor reports a consultancy/advisory role with Bayer, Sanofi, AstraZeneca, Dendreon, Constellation Pharmaceuticals, AAA, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Blue Earth Diagnostics, Myovant Sciences, Myriad Genetics, Novartis, Clarity Pharmaceuticals, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, Noxopharm, Clovis Oncology, Noria Therapeutics, Point Biopharma, TeneoBio, Telix Pharmaceuticals, and Theragnostics; travel expenses from Bayer, Johnson & Johnson, Sanofi, AstraZeneca, and Progenics; expert testimony for Sanofi; stocks/other ownership interests in Lilly, GlaxoSmithKline, Abbvie, Cardinal Health, United Health Group, PSMA Therapeutics, Clarity Pharmaceuticals, Noria Therapeutics, and Clovis Oncology; and research funding from Bayer, Sanofi, Endocyte, Merck, InVitae, Constellation Pharmaceuticals, AAA, AstraZeneca, Dendreon, SOTIO, Janssen, and Progenics. Chris Guise of Cancer Communications and Consultancy Ltd, Cheshire, U.K., provided medical writing assistance funded by Bayer. Lila Adnane (Bayer) provided editorial assistance. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Can 177Lu-PSMA be safely given to patients with mCRPC if they have previously received 223Ra, and is safety impacted depending on where 223Ra is positioned in the treatment sequence?
PERTINENT FINDINGS: In this real-world setting, 177Lu-PSMA had an acceptable safety profile in patients who had previously received 223Ra, with low rates of hematologic and overall AEs. Median OS from the first dose of 177Lu-PSMA was 13.2 mo and was similar irrespective of whether patients had received taxane-based chemotherapy before or after 223Ra or if the time between 223Ra and 177Lu-PSMA was less than 6 mo versus 6 mo or more.
IMPLICATIONS FOR PATIENT CARE: In patients with mCRPC and prior 223Ra therapy, 177Lu-PSMA had an acceptable safety profile and an effectiveness comparable to that seen in the VISION trial, irrespective of when patients had received prior 223Ra.
Footnotes
Published online Oct. 12, 2023.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml.
REFERENCES
- Received for publication July 13, 2023.
- Revision received September 17, 2023.
