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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

Open Access 04.03.2022 | Original Article

Matched-pair analysis of [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer

verfasst von: Philipp E. Hartrampf, Franz-Xaver Weinzierl, Andreas K. Buck, Steven P. Rowe, Takahiro Higuchi, Anna Katharina Seitz, Hubert Kübler, Andreas Schirbel, Markus Essler, Ralph A. Bundschuh, Rudolf A. Werner

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 9/2022

Abstract

Background

Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT.

Materials and methods

A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [¹⁷⁷Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [¹⁷⁷Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared.

Results

Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [¹⁷⁷Lu]Lu-PSMA I&T and five (9.1%) for [¹⁷⁷Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [¹⁷⁷Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [¹⁷⁷Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [¹⁷⁷Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89).

Conclusion

In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.

This article is part of the Topical Collection on Oncology - Genitourinary

Ralph A. Bundschuh and Rudolf A. Werner contributed equally.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Introduction

As the second most frequent malignancy in men worldwide, the annual incidence of prostate cancer (PC) is 1.4 million and accounts for > 375,000 deaths [1]. The transition from an androgen-dependent to a castration-resistant phenotype poses challenges for treating clinicians, especially in widespread diseases. Recent years have witnessed the introduction of novel therapeutic regimens for metastatic castration-resistant prostate cancer (mCRPC), including androgen receptor signalling inhibitors [2, 3] chemotherapeutics [4‐6], and prostate-specific membrane antigen (PSMA)-directed radioligand therapies (RLT), which are typically carried out with small-molecule, urea-based agents linked to the ß-emitting radionuclide lutetium-177 [7]. In this regard, recent prospective trials have shown remarkable outcomes after PSMA RLT in patients with mCRPC [8‐11]. For instance, the VISION trial reported a substantial prolongation of overall survival (OS) when compared to current standard-of-care therapy, along with an objective response rate in approximately half of the patients [12].

To date, PSMA-targeted RLT is mainly conducted with the two different agents, [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617 [7]. As shown in Fig. 1, the chemical structures of the two labelled peptides for PSMA-directed RLT show significant differences. Only the urea-binding motif of the two peptides is identical, but the majority of the two molecules show no structural similarity. On closer inspection, even the chelators are different: while in [¹⁷⁷Lu]Lu-PSMA-617, the peptide is linked to a DOTA chelator [13], in [¹⁷⁷Lu]Lu-PSMA I&T, the related DOTAGA chelator is used [14]. Of note, a recent dosimetry study reported on comparable mean absorbed tumour doses for both compounds [15]. In a preclinical setting, [¹⁷⁷Lu]Lu-PSMA-617 seems to be superior when compared to [¹⁷⁷Lu]Lu-PSMA I&T [16]. Head-to-head comparisons in patients, however, are still lacking [7]. In this two-centre, matched-pair analysis, we compared the toxicity and efficacy of [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617 for treatment of patients with mCRPC.

Materials and methods

Patient cohort

This retrospective study consisted of 55 patients who were treated with [¹⁷⁷Lu]Lu-PSMA I&T for mCRPC at the University Hospital Würzburg (Germany) and received at least two cycles of RLT. The matched cohort included 55 patients with mCRPC treated with at least two cycles of [¹⁷⁷Lu]Lu-PSMA-617 at the University Hospital Bonn (Germany). Matching criteria included age at the first cycle, Gleason score (categories: 6–7, 8–10, or unknown, [17]), baseline PSA values (0–50 ng/mL, 50–200 ng/ml, 200–600 ng/ml, and > 600 ng/mL), and previous taxane-based chemotherapies (CTx). Approvals were waived by the local Ethics Committees of Bonn and Würzburg due to the retrospective nature of this analysis (20210422 04).

Treatment protocol

Standardized institutional protocols for the execution of RLT were applied. In-house labelling was carried out for [¹⁷⁷Lu]-labelled PSMA ligands ([¹⁷⁷Lu]Lu-PSMA I&T (Würzburg) and [¹⁷⁷Lu]Lu-PSMA-617 (Bonn)). Radiosynthesis of [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617 have been described elsewhere [18, 19]. Identical treatment protocols at both study sites included administration of approximately 6.0 GBq of the PSMA ligand every 8 weeks with up to a maximum of 8 cycles, depending on the response to treatment [18, 19].

Toxicity and efficacy assessment

Standard blood collection included prostate-specific antigen (PSA) values, leukocytes, haemoglobin, platelets, creatinine, lactate dehydrogenase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase. By comparing with baseline parameters, toxicity was assessed at the last available cycle. Changes in blood cell counts and creatinine levels were also graded according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0) [20]. Efficacy was assessed by comparing OS between both cohorts.

Statistical analysis

Statistical analyses were performed using GraphPad Prism version 9.3.0 (GraphPad Software, San Diego, CA, USA). Descriptive data (including OS) are presented as median and range in parentheses. Since not all parameters were normally distributed (Shapiro–Wilk test), comparisons between the two cohorts were performed using Wilcoxon signed-rank test. For comparison of dichotomous variables, Fisher’s exact test was applied. OS was analysed using Kaplan–Meier curves and log-rank comparison. A P-value less than 0.05 was considered statistically significant.

Results

Patients’ characteristics were comparable for both cohorts

Overall, the median patient age at the first cycle of therapy was 71 (46–84) years for [¹⁷⁷Lu]Lu-PSMA I&T and 70 (43–86) years for [¹⁷⁷Lu]Lu-PSMA-617. The median Gleason score was 9 in both cohorts. For baseline PSA levels, no significant differences between the groups were observed ([¹⁷⁷Lu]Lu-PSMA I&T: 168.0 (5.0–3130) ng/ml, [¹⁷⁷Lu]Lu-PSMA-617: 145 (3.6–2360) ng/ml; P = 0.16). In addition, serum chemistry, blood counts, and previous therapies also did not differ between both groups. For preexisting comorbidities, only arterial hypertension differed significantly between both groups ([¹⁷⁷Lu]Lu-PSMA I&T: 56.4%, [¹⁷⁷Lu]Lu-PSMA-617: 27.3%; P = 0.004). In total, patients received a median of three RLT cycles of either [¹⁷⁷Lu]Lu-PSMA I&T or [¹⁷⁷Lu]Lu-PSMA-617 (P = 0.77). As such, neither cumulative administered activity ([¹⁷⁷Lu]Lu-PSMA I&T, 18.0 GBq; [¹⁷⁷Lu]Lu-PSMA-617, 19.0 GBq), nor median activity per cycle ([¹⁷⁷Lu]Lu-PSMA I&T, 6.0 GBq; [¹⁷⁷Lu]Lu-PSMA-617, 6.2 GBq) differed significantly (P > 0.05, respectively; Table 1).

Table 1

Baseline patient characteristics

	[¹⁷⁷Lu]Lu- PSMA I&T	[¹⁷⁷Lu]Lu-PSMA-617	P-value
Clinical variables
Age at first cycle of PSMA RLT (years)#	71 (46–84)	70 (43–86)	0.89
Time period between initial diagnosis and 1st RLT (months)	64.0 (9–246)	63 (4–241)	0.37
Treatment cycles per patient	3 (2–8)	3 (2–8)	0.77
Cumulative activity (GBq)	18.0 (10.4–49.2)	19.0 (7.9–45.8)	0.21
Activity per cycle (GBq)	6.0 (3.9–6.8)	6.2 (3.9–9.6)	0.11
Gleason score#	9 (6–10)	9 (6–10)	1.0
Baseline laboratory values
PSA (ng/ml)#	168 (5.0–3130)	145 (3.6–2360)	0.16
LDH (37 °C U/l)	269 (118–1105)	274 (147–2582)	0.13
Leukocytes (Tsd/µl)	6.0 (2.7–15.3)	6.4 (1.5–13.8)	0.46
Haemoglobin (g/dl)	11.5 (8.2–16.1)	11.6 (7.9–13.8)	0.34
Platelets (Tsd/µl)	245.0 (76.0–590)	226.0 (45.0–562)	0.27
Creatinine (mg/dl)	0.92 (0.60–1.92)	0.82 (0.48–2.12)	0.08
AST (37 °C U/l)	28.0 (15.0–62.0)	28.0 (14.0–114.0)	0.70
Gamma-GT (37 °C U/l)	32.1 (12.8–307.1)	33.0 (12.0–1130)	0.48
AP (37 °C U/l)	130 (31.0–1499)	139 (45.0–982)	0.65
Previous Treatments (%)
Radical prostatectomy	40.0	41.8	1.0
Primary radiation therapy to the prostate	16.4	18.2	1.0
Adjuvant radiation therapy	21.8	14.6	0.46
Salvage radiation therapy	18.2	9.1	0.27
Antihormonal treatment	100	100	1.0
Second generation antihormonal treatment (Abiraterone /Enzalutamide)	90.9	89.1	1.0
Chemotherapy#	72.4	72.4	1.0
Comorbidities (%)
Arterial hypertension	56.4	27.3	0.004
Preexisting renal disease	18.2	9.1	0.27
Diabetes mellitus	16.4	3.6	0.05

Abbreviations: PSA, prostate specific antigen; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; GammaGT, gamma-glutamyltransferase; AP, alkaline phosphatase

^# = matching criteria

Toxicity profiles revealed no relevant differences between both agents

During follow-up, patients treated with [¹⁷⁷Lu]Lu-PSMA I&T demonstrated a median decrease of leukocytes, haemoglobin, and platelets of 11.6%, 6.3%, and 12.1%, respectively. For [¹⁷⁷Lu]Lu-PSMA-617, comparable respective declines of 13.0%, 9.6%, and 12.8% were recorded. No significant difference was reached for a decrease between both agents. Creatinine levels increased slightly in both cohorts ([¹⁷⁷Lu]Lu-PSMA I&T, 4.9%; [¹⁷⁷Lu]Lu-PSMA-617, 4.2%; n.s.; Fig. 2). Compared to baseline, only one grade III anaemia (1.8%) was observed in the [¹⁷⁷Lu]Lu-PSMA I&T cohort and five grade III anaemia (9.1%) in the [¹⁷⁷Lu]Lu-PSMA-617 cohort. For the latter agent, there was also one grade III (1.9%) toxicity for platelets after the last cycle. Apart from that, no further grade III/IV toxicities were recorded for either agent (Fig. 3, Table 2).

Table 2

Classifications according to CTCAE vers. 5.0 for leukocytes, haemoglobin, platelets, and creatinine for patients treated with [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617 at baseline and after the last available cycle. *For [¹⁷⁷Lu]Lu-PSMA-617, blood values were collected, with only platelets missing in 2 subjects. ^#For [¹⁷⁷Lu]Lu-PSMA-617, there were five grade III toxicities for haemoglobin and one grade III toxicity for platelets after the last cycle. At baseline, however, one event for each blood value was already recorded, and thus, the total number of toxicities in this cohort only increased by four after the last cycle for haemoglobin and remained stable for platelets. No other grade III/IV toxicities occurred for both compounds

		[¹⁷⁷Lu]Lu-PSMA I&T					[¹⁷⁷Lu]Lu-PSMA-617
		Grade 0	Grade I	Grade II	Grade III	Grade IV	Grade 0	Grade I	Grade II	Grade III	Grade IV
Leukocytes	Baseline	42/55 (76.4%)	12/55 (21.8%)	1/55 (1.8%)	0.0	0.0	42/55 (76.4%)	12/55 (21.8%)	0.0	1/55 (1.8%)	0.0
Leukocytes	Last cycle	30/55 (54.5%)	21/55 (38.2%)	4/55 (7.3%)	0.0	0.0	29/55 (52.7%)	23/55 (41.8%)	3/55 (5.5%)	0.0	0.0
Haemoglobin	Baseline	5/55 (9.1%)	39/55 (70.9%)	11/55 (20.0%)	0.0	0.0	0.0	41/55 (74.5%)	13/55 (23.6%)	1/55 (1.8%)	0.0
Haemoglobin	Last cycle	4/55 (7.3%)	31/55 (56.4%)	19/55 (34.5%)	1/55 (1.8%)	0.0	1/55 (1.8%)	26/55 (47.3%)	23/55 (41.8%)	5/55 (9.1%)^#	0.0
Platelets	Baseline	53/55 (96.4%)	2/55 (3.6%)	0.0	0.0	0.0	49/55 (89.1%)	5/55 (9.1%)	0.0	1/55 (1.8%)	0.0
Platelets	Last cycle*	44/55 (80.0%)	7/55 (12.7%)	4/55 (7.3%)	0.0	0.0	40/53 (75.5%)	12/53 (22.6%)	0.0	1/53 (1.9%)^#	0.0
Creatinine	Baseline	44/55 (80.0%)	9/55 (16.4%)	2/55 (3.6%)	0.0	0.0	48/55 (87.3%)	5/55 (9.1%)	2/55 (3.6%)	0.0	0.0
Creatinine	Last cycle	42/55 (76.4%)	11/55 (20.0%)	2/55 (3.6%)	0.0	0.0	46/55 (83.6%)	4/55 (7.3%)	5/55 (9.1%)	0.0	0.0

Overall survival is also comparable for both agents

Median OS was 12 months for patients treated with [¹⁷⁷Lu]Lu-PSMA I&T and 13 months for patients treated with [¹⁷⁷Lu]Lu-PSMA-617 (P = 0.89; Fig. 4).

Discussion

In this matched-pair analysis, we investigated the two most commonly applied urea-based, small-molecule inhibitors of PSMA, namely PSMA-617 and PSMA I&T. We carefully matched patients based on age, Gleason score, and PSA levels. Pre-therapeutic CTx has also been suggested to have a relevant impact on outcome [21] and, thus, we also matched according to this previous treatment regimen. After having controlled for such key variables, toxicity assessments revealed low rates of side effects, with one grade III anaemia for [¹⁷⁷Lu]Lu-PSMA I&T and five grade III anaemia as well as one grade III thrombopenia for [¹⁷⁷Lu]Lu-PSMA-617. Moreover, OS for [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA I&T did not significantly differ.

Multiple prospective trials have reported a favourable outcome for [¹⁷⁷Lu]Lu-PSMA-617, including prolonged OS when compared to standard-of-care [12], and pain reduction in patients with disease progression after conventional treatment [9]. As the second most commonly used RLT agent [7], [¹⁷⁷Lu]Lu-PSMA I&T has been utilized in retrospective studies demonstrating beneficial outcomes in heavily pre-treated mCRPC patients [22]. Results of a currently recruiting, a prospective clinical trial investigating the performance of this agent as a last-line option will be announced in due course [23]. Despite the encouraging results for both radiopharmaceuticals, head-to-head comparisons are still scarce [7]. In this matched-pair analysis focusing on outcome and toxicity, respective Kaplan–Meier curves for OS revealed no significant differences between patients treated with [¹⁷⁷Lu]Lu-PSMA I&T (median 12 months) and [¹⁷⁷Lu]Lu-PSMA-617 (median 13 months). This is in line with a recent dosimetry study comparing both ¹⁷⁷Lu-labelled, PSMA-directed small molecules. Although no matching was conducted, [¹⁷⁷Lu]Lu-PSMA I&T had increased initial uptake in metastatic sites of disease, while the residency time and the effective half-life was longer for [¹⁷⁷Lu]Lu-PSMA-617. Nonetheless, those findings had no relevant impact on the mean absorbed tumour doses ([¹⁷⁷Lu]Lu-PSMA I&T: 5.8 Gy/GBq, [¹⁷⁷Lu]Lu-PSMA-617: 5.9 Gy/GBq) [15], which may explain comparable outcome benefits for both agents observed in our study.

No grade III/IV renal toxicities occurred during follow-up. For hematotoxicity, we observed only one patient with new grade III anaemia for [¹⁷⁷Lu]Lu-PSMA I&T and five patients with new grade III anaemia for [¹⁷⁷Lu]Lu-PSMA-617. For [¹⁷⁷Lu]Lu-PSMA-617, there was also one grade III toxicity for platelets. Apart from that, no further grade III/IV toxicities were recorded for either agent. Taken together, this study corroborates previous reports investigating side effects in patients treated with [¹⁷⁷Lu]Lu-PSMA-617 [7, 10‐12, 24] or [¹⁷⁷Lu]Lu-PSMA I&T [25], which also reported promising safety profiles for both agents. As such, the treating physician can have certainty that both [¹⁷⁷Lu]Lu-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA I&T achieve equivalent outcome benefits along with comparable low toxicity profiles.

For PSMA RLT, the structures of the two labelled peptides show relevant differences (Fig. 1) [13, 14]. Furthermore, murine studies performing head-to-head comparisons with both radiotracers demonstrated more favourable biodistribution for [¹⁷⁷Lu]Lu-PSMA-617 [16]. In light of these preclinical findings and the structural variances among both agents, the similar efficacy and toxicity of the two radiopharmaceuticals were not necessarily expected.

This study has limitations. Striving for an accurate matching, and despite including a total of 110 mCRPC patients, the sample size was rather small. The grouping of patients by original Gleason score categories (i.e. Gleason 6–7 and Gleason 8–10) allowed for adequate matching [17]. Nonetheless, future studies are needed to compare both agents in an even more controlled environment, preferably in a prospective setting. In this regard, such efforts may then adjust for further important variables, including dosimetry aspects, biodistribution, radiotracer preparation, and logistics. Moreover, compared to the VISION trial, which reported on an OS of 15.3 months for [¹⁷⁷Lu]Lu-PSMA-617 after a median of five cycles of RLT [12], our patients underwent only three cycles of treatment, thereby explaining our shorter OS of only 13 months for this agent. As such, we did not follow current treatment standards as defined by the VISION trial, and future studies should also include patients with a higher number of cycles [12].

Conclusions

Investigating the most commonly used agents for PSMA-targeted RLT, [¹⁷⁷Lu]Lu-PSMA I&T and [¹⁷⁷Lu]Lu-PSMA-617, this matched-pair analysis demonstrates that toxicity profiles of both compounds are comparable, with very low rates of clinically relevant toxicities. In addition, both radiopharmaceuticals are similarly effective in patients with mCRPC.

Declarations

Institutional Review Board statement

The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived for this study by the local Ethics Committee due to the retrospective character of the study (# 20210422 04).

All procedures have been conducted as part of clinical routine care. Informed consent has been obtained from all subjects.

Conflict of interest

R.A.B. is a consultant for Bayer Healthcare (Leverkusen, Germany) and Eisai GmbH (Frankfurt, Germany). R.A.B. has a noncommercial research agreement and is on the speakers’ list of Mediso Medical Imaging (Budapest, Hungary). M.E. is a consultant for Bayer Healthcare (Leverkusen, Germany), Eisai GmbH (Frankfurt, Germany), IPSEN, and Novartis.

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Titel: Matched-pair analysis of [177Lu]Lu-PSMA I&T and [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer
verfasst von: Philipp E. Hartrampf
Franz-Xaver Weinzierl
Andreas K. Buck
Steven P. Rowe
Takahiro Higuchi
Anna Katharina Seitz
Hubert Kübler
Andreas Schirbel
Markus Essler
Ralph A. Bundschuh
Rudolf A. Werner
Publikationsdatum: 04.03.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 9/2022
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05744-6

Springer Medizin

Abstract

Background

Materials and methods

Results

Conclusion

Publisher's Note

Introduction

Materials and methods

Patient cohort

Treatment protocol

Toxicity and efficacy assessment

Statistical analysis

Results

Discussion

Conclusions

Declarations

Institutional Review Board statement

Consent to participate

Conflict of interest

Publisher's Note

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