Combination Metastasis-Targeted External Beam Radiation Therapy With ¹⁷⁷Lu-PSMA-617 in Patients With Advanced Castration-Resistant Prostate Cancer

Abstract

Purpose:

¹⁷⁷Lu-PSMA-617 (LuPSMA) is an effective radiopharmaceutical therapy for patients with metastatic castration-resistant prostate cancer. While LuPSMA can treat disseminated disease, additional localized control of metastatic disease may be required. Metastasis-targeted external beam radiation therapy (M-EBRT) can be an effective adjunct. However, the indications, efficacy, and safety/toxicity of combining M-EBRT with LuPSMA are unclear. Here, we report our experience with M-EBRT in patients receiving LuPSMA and assess M-EBRT’s ability for local disease control and palliation.

Methods and Materials:

This retrospective institutional review board-exempted study reviewed patients treated with LuPSMA at a multi-institutional academic cancer center within the first 2 years after United States Food and Drug Administration’s approval, receiving contemporaneous M-EBRT. Clinical factors driving the use of M-EBRT were analyzed.

Results:

Treatment courses of 261 patients receiving LuPSMA were reviewed; 52 patients received M-EBRT contemporaneously. M-EBRT was administered for intracranial/epidural disease (n = 22/52; 42%), bone pain palliation (n = 17/52; 33%), prevention of pathological fractures (n = 12/52; 23%), and 12% (n = 6/52) for various other indications. M-EBRT timing varied among patients, with 54% (n = 28/52) receiving M-EBRT before, 27% (n = 14/52) after, and 13% (n = 7/52) during LuPSMA therapy. EBRT was mostly well tolerated, although lymphopenia was commonly experienced. Most patients (n = 32/52; 62%) had symptom relief following M-EBRT. Symptom relief post−M-EBRT was 68%, 85%, and 50%, and mortality rates were 32%, 29%, and 57% for patients receiving EBRT before, during, and after LuPSMA treatment, respectively, albeit not statistically significant (P > .23). Prostate-specific antigen (PSA)50 (decrease in PSA by 50% during treatment) response in this patient population was 41% compared with 50% in the general LuPSMA population, but the magnitude of PSA response was heterogeneous (P = .27).

Conclusions:

In our experience, M-EBRT was used effectively with LuPSMA therapy for local tumor control and symptom management, especially for localized osseous and central nervous system lesions, and with good tolerability. M-EBRT may be an important adjunct treatment modality that facilitates the initiation and/or continuation of LuPSMA.

Introduction

Prostate cancer accounts for 15% of all malignancies and is the second leading cause of cancer-related death in men in the United States. The incidence of prostate cancer worldwide is expected to rise from 1.4 million annually in 2020 to 2.9 million by 2040.¹ While outcomes for cancer localized to the prostate are generally good, they are much poorer for metastases, with 5-year survival ~30%.^2–5 Chemo, hormonal, and immunotherapy options for advanced prostate cancer demonstrate limited efficacy and cause significant systemic toxicity.^6–9 Radiopharmaceutical therapy (RPT) is an emerging systemic treatment modality for disseminated metastases with favorable therapeutic profiles.¹⁰ In particular, ¹⁷⁷Lu-PSMA-617 (¹⁷⁷Lu-vipivotide tetraxetan, LuPSMA) was recently United States Food and Drug Administration−approved² for patients with metastatic castration-resistant prostate cancer (mCRPC) and has become a key option for patients with advanced disease.

LuPSMA can be effective for patients with disease burden refractory to chemotherapy or when chemotherapy is not well tolerated. However, instances arise where specific localized disease sites or presenting clinical symptoms may require more immediate disease control than what LuPSMA alone can provide or jeopardize treatment continuation while on LuPSMA despite effective disease control elsewhere. For these cases, the availability of targeted and localized treatment adjuncts that can be used with LuPSMA would be highly desirable.

External beam radiation therapy (EBRT) is an effective localized treatment option for primary prostate cancer and for patients with low-volume metastatic prostate cancer.^11–13 Metastasis-directed EBRT (M-EBRT) is used for disease palliation in mCRPC patients,¹⁴ but the indications, tolerability, and outcomes for its use in combination with RPT, such as the beta particle emitting LuPSMA, are, to our knowledge, unclear. Therefore, the objective of this study was to understand clinical indications that guide the contemporaneous use of M-EBRT for patients being treated with LuPSMA in the real-world set-ting, as well as to evaluate the efficacy and safety profile of their combination.

Methods and Materials

This retrospective chart review was deemed exempt by the local institutional review board, and the requirement for consent was waived. The study schema is outlined in Fig. 1. The medical records of patients with mCRPC considered for LuPSMA across a multi-institutional National Cancer Institute (NCI)-designated cancer center from May 2022 to March 2024 were reviewed. Patients with incomplete clinical data, such as longitudinal prostate-specific antigen (PSA), were excluded from downstream analysis. Patients were included in the study if they received at least 1 cycle of LuPSMA and were treated with M-EBRT within any of the following timeframes: (1) up to 6 months before the initiation of LuPSMA therapy, (2) at any time point during the LuPSMA treatment course, and (3) within 6 months after receiving their last LuPSMA dose. The 6-month window was chosen to enable the assessment of potential cumulative toxicities incurred when LuPSMA is given in relative proximity to M-EBRT. LuPSMA dosing adhered to United States Food and Drug Administration−approved indications, guided by VISION.²

Figure 1.

Study schema.

Abbreviations: EBRT = external beam radiation therapy; LuPSMA = ¹⁷⁷Lu-PSMA-617; mCRPC = metastatic castration-resistant prostate cancer.

Specific clinical data abstracted for analysis are detailed in Table E1. Clinical data included demographic information, laboratory and imaging assessment of prostate cancer burden, systemic toxicity during LuPSMA/M-EBRT cycles, prior and current medical therapies, and the timing and technique of LuPSMA and M-EBRT treatments. The electronic medical record was reviewed to understand the indications and subjective symptoms driving the use of M-EBRT for these patients and how these were impacted by the treatment combination.

Semiquantitative assessment of outcomes

Where possible, standard metrics to assess treatment response outcomes and toxicity were adopted, including PSA50 (decrease in PSA by 50% over the course of LuPSMA/M-EBRT treatment), Common Terminology Criteria for Adverse Events (CTCAE), and Patient-Reported Outcome (PRO) version 5.0, to grade radiation-related toxicity.^15,16 In our analysis, we included all 52 patients who received LuPSMA treatment, regardless of their initial PSA levels. Of note, patients with very low initial PSA values (≤0.03 ng/mL, n = 3) were excluded from the analysis of PSA50 rates to avoid skewing results from likely non−PSA-producing cancers. Additionally, subjective clinical responses to M-EBRT were assessed based on the scales shown in Table E2.¹⁷ Extraction and assessment of the clinical data were cross-checked across multiple researchers to ensure concordance during data collection.

Statistical analysis

Descriptive statistics were employed to systematically analyze the clinical and treatment characteristics of eligible patients. Age and total M-EBRT dose were collected as continuous covariates, with median and range values calculated to summarize their distribution. For categorical variables, such as concurrent steroid treatment with EBRT, symptom relief post−M-EBRT (as assessed using the symptom assessment scales detailed in Table E2), previous systemic treatments, count tabulation, and percentages were used to report descriptive statistics. Significant differences in categorical outcome proportions across the different timings of M-EBRT in relation to LuPSMA administration and, in the case of PSA50, between M-EBRT−treated groups and the general LuPSMA population treated during a similar time period were assessed using Fisher’s exact test. All statistical analyses were performed with SPSS (version 27, IBM) and/or GraphPad Prism (version 10). A P value of less than .05 was considered statistically significant.

Results

Of the 261 patients who received LuPSMA during the defined study period, 52 subjects received contemporaneous EBRT with LuPSMA and met our inclusion criteria. Their baseline characteristics are presented in Table 1. The mean PSA at the onset of LuPSMA treatment was 273 ng/mL (range, 0.02–4460). Patients received a median of 4 (range, 1–6) cycles of LuPSMA, with 27% (14/52) of patients completing the typical 6-dose course. Overall tumor burden, PSA levels, and tumor sites requiring M-EBRT varied between patients, and patients received tailored M-EBRT for their specific disease conditions, as summarized in Table 2. The median total dose of M-EBRT was 2400 cGy (range, 400–6160), and the median number of fractions was 5 (range, 1–28). The median follow-up for patients alive at the last follow-up was 170 days, whereas the median follow-up for the entire cohort was 160 days.

Table 1.

Baseline characteristics of the patients

Characteristic
Age (years, median, range)	72 (53–84)
Prostate-specific antigen (ng/mL, mean, median, range)	259, 21 (0.02–4460)
	n (%, total =52 patients)
Concurrent steroid treatment with M-EBRT
Yes	37 (71%)
No	15 (29%)
Symptom relief post M-EBRT within 6 months of LuPSMA
Positive response	32 (62%)
Negative response	9 (17%)
No response	4 (8%)
Missed	7 (13%)
Prior systemic treatments
Androgen deprivation or androgen receptor inhibition therapy	52 (100%)
*Chemotherapy	52 (100%)
†PARP inhibitors	4 (8%)
Clinical trial therapies	3 (6%)
‡Immunotherapy	5 (10%)
223Radium chloride	8 (15%)
Prior Lines of Systemic Treatments
≥2	2 (3%)
≥3	11 (21%)
≥4	15 (28%)
≥5	24 (46%)
LuPSMA administration
1 cycle	3 (6%)
2 cycles	13 (25%)
3 cycles	9 (17%)
4 cycles	11 (21%)
5 cycles	2 (4%)
6 cycles	14 (27%)

Abbreviations: LuPSMA = ¹⁷⁷Lu-PSMA-617; M-EBRT = metastasis-targeted external beam radiation therapy.

^*Docetaxel, cabazitaxel, and carboplatin.

^†Olaparib and talazoparib.

^‡Pembrolizumab and sipuleucel-T.

Table 2.

M-EBRT Details

Total Dose (cGy)
Mean (standard deviation)	2527 (1009)
Median (range)	2400 (400–6160)
Number of fractions
Mean (standard deviation)	6.1 (4.4)
Median (range)	5 (1–28*)
Radiation Targets	n (%, total = 86 targeted sites)
Targets per patient (median, range)	1 (1–7)
CNS (Brain and Spine)	11 (13%)
Lungs	2 (2%)
Retroperitoneal Lymph Nodes	1 (1%)
Prostate	1 (1%)
Bone
Clavicle	1 (1%)
Extremity	14 (16%)
Pelvis	9 (10%)
Ribs	7 (8%)
Skull	1 (1%)
Spine	39 (45%)
Radiation Technique
3-D CRT	39 (45%)
VMAT/IMRT	17 (20%)
SBRT	11 (13%)
SRS	4 (5%)
Unknown	15 (17%)

Abbreviations: CNS = central nervous system; 3D CRT = 3 dimensional confromal radiation therapy; IMRT = intensity modulated radiation therapy; VMAT = volume modulated arc therapy; SBRT = stereotactic beam radiation therapy; SRS = stereotactic radio surgery.

^*One patient received 28 fractions to a lymph node in the pelvic region; at the same time, they were receiving 5 fractions to a lesion in their pelvic bone.

M-EBRT was administered across multiple indications and locations

Specific indications driving the use of M-EBRT in patients receiving LuPSMA are presented in Table 3 and Table E3. M-EBRT was administered to 42% (n = 22/52) of patients for the management of lesions in the central nervous system (CNS), 33% (n = 17/52) for palliation of bone metastasis-related pain, 23% (n = 12/52) for the prevention of impending pathological fractures, and 12% (n = 6/52) for other indications. More than 1 of these indications applied to 10% (n = 5/52) of patients. M-EBRT was most commonly administered to osseous and epidural spinal lesions (73%, n = 38/52). Less common target sites included the ribs (6%, n = 3/52), lungs, and lymph nodes (each 4%, n = 2/52).

Table 3.

Indications for M-EBRT in patients with mCRPC receiving LuPSMA therapy

	Timing of M-EBRT administration relative to LuPSMA
Indication for M-EBRT	Before LuPSMA only (n (% patients))	During LuPSMA only (n (% patients))	After LuPSMA only (n (%patients))	During and After LuPSMA (n (% patients))	Before and After LuPSMA (n (% patients))	During and Before LuPSMA (n (% patients))	Total (n (% all M-EBRT patients * ))
Management of intracranial and spinal cord metastatic (CNS) disease	9 (32%)	2 (29%)	8 (57%)	1 (100%)	1 (100%)	1 (100%)	22 (42%)
Palliation of bone metastasis-related pain	10 (36%)	3 (43%)	3 (21%)	1 (100%)	0 (0%)	0 (0%)	17 (33%)
Prevention of impending pathological fractures	7 (25%)	1 (14%)	3 (21%)	0 (0%)	1 (100%)	0 (0%)	12 (23%)
Other indications
Gross hematuria due to eroding tumor on cystoscopy	1 (4%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1 (2%)
Continuous rise in PSA	0 (0%)	1 (14%)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	1 (2%)
In order to get off of the systemic therapy	0 (0%)	0 (0%)	1 (7%)	0 (0%)	0 (0%)	0 (0%)	1 (2%)
High disease burden in bone and lymph node	2 (7%)	0 (0%)	1 (7%)	0 (0%)	0 (0%)	0 (0%)	3 (6%)
Total indications *	29	7	16	2	2	1	57
Total patients	28	7	14	1	1	1	52

Abbreviations: CNS = central nervous system; LuPSMA = ¹⁷⁷Lu-PSMA-617; M-EBRT = metastasis-targeted external beam radiation therapy; PSA, prostate-specific antigen.

^*Note that of the 52 patients studied, 5 were deemed to have 2 indications motivating the use of M-EBRT.

Contemporaneous M-EBRT can be applied across all stages of LuPSMA treatment, especially for addressing CNS disease

M-EBRT was mostly used for local symptom control before the initiation of LuPSMA (53%, n = 28/52). Treatment occurred at a median of 68 days before the first LuPSMA dose (range, 2–183 days) and was especially used for CNS lesions (32%, n = 9/28), focal bone pain (36%, n = 10/28), and prophylaxis for impending fractures (25%, n = 7/28). M-EBRT was used in 23% (n = 14/52) of patients after their LuPSMA course ended (median, 55 days; range, 13–153 days) and also predominantly to manage CNS lesions and bone pain. M-EBRT was less used during the LuPSMA course (15%, n = 7/52; onset from most recent LuPSMA dose: range, 5–90 days; administration of subsequent LuPSMA dose: range, 7–34 days), most commonly for the acute management of bone metastasis-related pain (43%, n = 3/7). A smaller number of patients (6%, n = 3/52) received multiple courses of M-EBRT throughout their LuPSMA treatment course at different timeframes.

Toxicity profile of combined M-EBRT/LuPSMA

Detailed toxicity outcomes of patients receiving contemporaneous M-EBRT and LuPSMA are provided in Table 4. Toxicity was assessed using the CTCAE and PRO-CTCAE criteria. In our M-EBRT/LuPSMA cohort, hematologic toxicities were observed at varying levels of severity. These included lymphopenia (8%, n = 4/52 at CTCAE = 1 increasing to 12%, n = 6/52 at both CTCAE = 2 and CTCAE ≥ 3), thrombocytopenia (4%, n = 2/52 at CTCAE ≥ 3), and neutrophilia (4%, n = 2/52 at CTCAE ≥ 3). Other, less severe symptoms (8%, n = 4/52, PRO-CTCAE = 1) experienced included nausea and dysphagia.

Table 4.

PRO-CTCAE and CTCAE =1, = 2, and ≥3 by individual items

Symptoms	PROCTCAE =1	Signs	CTCAE =1
Difficulty swallowing	4 (8%)	Anemia	3 (6%)
Hoarseness	2 (4%)	Thrombocytopenia	2 (4%)
Decreased appetite	1 (2%)	Leukopenia	3 (5%)
Nausea	4 (8%)	Lymphopenia	4 (8%)
Vomiting	2 (4%)	Neutropenia	1 (2%)
Diarrhea	2 (4%)
Weight loss	1 (2%)
Back pain	1 (2%)
Sacral pain	1 (2%)
Numbness and tingling	1 (2%)
Upper extremity weakness	2 (4%)
Lower extremity weakness	2 (4%)
Fatigue	2 (4%)
	PROCTCAE =2		CTCAE =2
Generalized muscle weakness	1 (2%)	Anemia	1 (2%)
Nausea	2 (4%)	Thrombocytopenia	1 (2%)
Vomiting	1 (2%)	Thromboembolic event	1 (2%)
Constipation	1 (2%)	Lymphopenia	6 (12%)
Back pain	2 (4%)	Leukopenia	1 (2%)
Swelling	1 (2%)	Neutropenia	1 (2%)
Numbness and tingling	1 (2%)	Neutrophilia	5 (10%)
Paresthesia	1 (2%)	Dehydration	1 (2%)
Localized edema	1 (2%)	Paresthesia	1 (2%)
Upper extremity weakness	1 (2%)	Shingles	2 (4%)
Lower extremity weakness	2 (4%)	General Muscle Weakness	1 (2%)
Fatigue	2 (4%)
	PROCTCAE ≥3		CTCAE ≥3
Constipation	1 (2%)	Thrombocytopenia	2 (4%)
Diarrhea	1 (2%)	Lymphopenia	6 (12%)
Generalized muscle weakness	1 (2%)	Neutrophilia	2 (4%)
Dizziness	1 (2%)	Leukocytosis	1 (2%)
Upper extremity weakness	1 (2%)	General Muscle Weakness	1 (2%)
Insomnia	1 (2%)

Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; PRO = Patient-Reported Outcome.

M-EBRT can provide local symptom control, albeit without appreciable long-term systemic disease control

Overall, M-EBRT was effective at providing symptom relief in 62% (n = 32/52) of patients (Tables E2 and E4), especially those with osseous lesions, who all achieved symptom relief (n = 17/17). However, M-EBRT was ineffective in some patients, with 8% (n = 4/52) of patients reporting that their symptoms worsened. Some patients experienced disease progression at the irradiated site despite M-EBRT treatment (17%, n = 9/52). Notably, none of the patients who received M-EBRT for pathologic fracture prophylaxis (23%, n = 12/52) developed fracture at a median of 5 months (range, 5–596 days) follow-up post−M-EBRT. No significant association between when M-EBRT was applied in relation to LuPSMA and whether symptom relief occurred was also noted (P = .85).

PSA response across our patient cohort was markedly heterogeneous. At any time during M-EBRT/LuPSMA therapy, 41% (20/49, excluding the 3 patients whose initial PSA ≤ 0.03 ng/mL) of patients achieved PSA50 − this was slightly lower but not significantly different compared with all the patients receiving LuPSMA during this period (PSA50 of a subset of the general population treated: 50% [122/244], P = .27; Table E4). No correlation between PSA50 (P = .97) or mortality status (P = .25) was observed when patients were stratified by when they received M-EBRT in relation to LuPSMA.

Discussion

Our experience demonstrates that contemporaneous M-EBRT is a viable palliative treatment strategy for local metastasis control in patients with mCRPC receiving LuPSMA, especially for managing CNS disease, bone pain palliation, and pathological fracture prevention.¹⁸ Notably, all patients receiving M-EBRT for fracture prevention did not develop fractures within the median 5-month follow-up period after M-EBRT onset. This compares favorably with previous reports,¹⁹ including the Radium-223 alpha Emitter Agent in Safety Study in mCRPC popUlation for long-teRm Evaluation (REASSURE) trial (NCT02141438), which reported concomitant M-EBRT use in 5% (n = 76/1465) of mCRPC patients receiving ²²³radium, primarily for pain palliation.²⁰ The incidence of fracture reported in the REASSURE (5%, n = 70/1465) and Alpharadin in Symptomatic Prostate Cancer; NCT00699751 (ALYSMPCA) (4%, n = 24/564) trials was higher than in our cohort, although the correlation between radiation exposure and skeletal events was not investigated in their analyses.^20,21 While localized control of CNS disease was more heterogeneous in our cohort, patients receiving M-EBRT for this indication before or during LuPSMA treatment did enable them to receive RPT, which may be an important adjunct treatment strategy to allow LuPSMA to be administered safely. Recent studies have demonstrated that lower beta-emitting radio-nuclides, such as ¹⁷⁷Lu, have dosimetry characteristics suitable for the treatment of CNS lesions,²² and no significant neurotoxicity was observed in our patient cohort. While the combination of ²²³radium and M-EBRT has been studied in the REASSURE trial, where 6% (n = 91/1465) of patients received radiation therapy during ²²³radium treatment,²⁰ the specific combination of LuPSMA therapy with focal M-EBRT has not been systematically investigated. Wei et al²³ treated 2 mCRPC patients with PSMA-positive intracranial metastases using 3 to 4 cycles of LuPSMA together with local M-EBRT. This combination resulted in a notable reduction in the size and Prostate-specific membrane antigen (PSMA) expression of all metastatic sites, with the intracranial lesions exhibiting a significant regression.

Ionizing radiation can confer significant and sustained hematologic toxicity and is a key concern when M-EBRT is combined with LuPSMA. Given that our patients had received multiple lines of treatment before LuPSMA, we anticipated that they might harbor more baseline hematologic dysfunction and experience more hematologic toxicities when receiving combined radiation. However, this was not typically the case, although lymphopenia was most commonly observed, similar to recent reports of patients receiving EBRT alone.²⁴ To the best of our knowledge, no studies have directly investigated the combined toxicity profile of M-EBRT and LuPSMA in patients with mCRPC. Grkovski et al²⁵ explored the combination of M-EBRT with LuPSMA in patients with castration-sensitive oligometastatic prostate cancer, finding that 83% (n = 5/6) of patients experienced grade 1 and 33% (n = 2/6) experienced grade 2 toxicities (transient anemia and hyperbilirubinemia), with no grade 3 or higher toxicities observed when M-EBRT was combined with LuPSMA. By comparison, 31% of patients in our study experienced grade 3 hematological toxicities. Despite this, the toxicity rates in our cohort were similar to those reported in the VISION and TheraP trials (Table E5).^2,26 This suggests that combined M-EBRT/LuPSMA has an acceptable toxicity profile, similar to LuPSMA monotherapy.

The primary role of M-EBRT in our context is disease palliation, as opposed to regression and cure, and no significant impact on the PSA50 and mortality rates was observed compared with LuPSMA alone. Nevertheless, some preclinical studies show the promise of this combination for growth delay and control.^27,28 Conceivably, this approach will likely be more successful in patients with limited/oligometastatic tumor burden, with several patient trials ongoing in this setting (NCT05079698, NCT05162573, and NCT05496959). Results from our study may provide helpful information to guide the design of these and other similar studies²⁷ to maximize the therapeutic index.

The main limitations of our study were its retrospective design and relatively small sample size, presenting a range of disease burdens. Variations in the timing and dose of the M-EBRT techniques used limited direct dosimetric comparison across patients. While a direct comparison with a matched LuPSMA cohort who did not receive M-EBRT was not performed, the toxicity profile of our patients was comparable to those reported in the key LuPSMA clinical trials performed to date in a similar patient population. Furthermore, it is important to note that a median follow-up period of 5 months is short; the long-term efficacy and safety of this combined treatment and a direct comparison between treatment groups need to be further studied. Nevertheless, our reported experiences likely span the range of clinical scenarios typically encountered by LuPSMA patients presenting as candidates for combined M-EBRT.

Conclusions

In summary, M-EBRT can be effectively used as an adjunctive palliative treatment strategy for localized disease management in patients being considered for LuPSMA, during their LuPSMA, or in the immediate post-LuPSMA treatment period with an acceptable toxicity profile similar to that encountered with either modality alone. While it did not significantly impact long-term tumor control in patients with advanced mCRPC, M-EBRT generally provided the desired symptomatic relief and was especially useful for pathologic fracture prophylaxis. Further investigation is warranted to understand the long-term toxicity and disease control using M-EBRT/LuPSMA, especially in patients at earlier stages of prostate cancer.

Supplementary Material

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.prro.2025.03.010.