Pretherapeutic Comparative Dosimetry of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T in Patients with Metastatic Castration-Resistant Prostate Cancer

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Abstract

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with ¹⁸F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for ¹⁷⁷Lu-rhPSMA-7.3, which has shown higher tumor uptake than ¹⁷⁷Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2–3 times higher for ¹⁷⁷Lu-rhPSMA-7.3 than for ¹⁷⁷Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for ¹⁷⁷Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. ¹⁷⁷Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of ¹⁷⁷Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Treatment of metastatic castration-resistant prostate cancer (mCRPC) remains challenging. ¹⁷⁷Lu-PSMA radioligand therapy (RLT) is an option with a variety of different prostate-specific membrane antigen (PSMA) ligands developed in recent years (1). Several prospective and retrospective studies proved that ¹⁷⁷Lu-PSMA (using either PSMA-617 or PSMA I&T) had substantial antitumor effects (2,3). Most recently, the VISION trial showed longer median radiographic progression-free survival (8.7 vs. 3.4 mo) and overall survival (15.3 vs. 11.3 mo) for ¹⁷⁷LuPSMA-617 versus the standard of care, respectively, in PSMA-positive mCRPC after the use of taxane and next-generation androgen receptor signaling inhibitor agents (4).

For the assessment of new radiopharmaceuticals, dosimetry is essential to link the potential range of injected activities with therapeutic responses and possible side effects. For example, PSMA ligands can exhibit intense tracer accumulation in some normal organs, such as the kidneys. Dosimetric results have been published for the theranostic DOTA-conjugated PSMA ligands ¹⁷⁷Lu-PSMA-DKFZ-617 and ¹⁷⁷Lu-PSMA I&T (5), including both pretherapeutic (6) and posttherapeutic (7–10) evaluations.

Recently, a class of radiohybrid PSMA (rhPSMA) ligands were developed. They are theranostic agents allowing both fluorination and labeling with radiometals (11–14). Preclinical data have proposed that the single diastereoisomer ¹⁸F-rhPSMA-7.3 is the most promising clinical candidate (15,16). ¹⁸F-rhPSMA-7.3 is currently in 2 phase 3 trials for PET imaging of primary (NCT04186819) and recurrent (NCT04186845) prostate cancers. Most recently, promising preclinical data on ¹⁷⁷Lu-rhPSMA-7.3 in comparison to ¹⁷⁷Lu-PSMA I&T were published (16).

Here, we present a retrospective analysis exploring the potential of ¹⁷⁷Lu-rhPSMA-7.3 in comparison to ¹⁷⁷Lu-PSMA I&T for endoradiotherapy in mCRPC. We used pretherapeutic comparative dosimetry data for normal organs and tumor lesions.

MATERIALS AND METHODS

Patients and Rationale for Comparative Dosimetry

According to current German guidelines, mCRPC patients after chemotherapy and novel antiandrogen therapy can be considered for ¹⁷⁷Lu-PSMA RLT after interdisciplinary tumor board discussion (17). All patients in the presented analysis had undergone chemotherapy and novel antiandrogen therapy before ¹⁷⁷Lu-PSMA.

Patients were informed that there are no approved PSMA-targeted therapies but that preliminary preclinical and clinical data support the antitumor activity of ¹⁷⁷Lu-PSMA I&T. Additionally, information about preclinical data showing higher uptake of ¹⁸F-rhPSMA-7.3 and higher absorbed doses of ¹⁷⁷Lu-rhPSMA-7.3 in tumors (14,16), indicating higher radiation doses to tumor tissue of ¹⁷⁷Lu-rhPSMA-7.3 than of ¹⁷⁷Lu-PSMA I&T for clinical use, was provided.

Patients were offered pretherapeutic administration of both ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-rhPSMA-7.3 to determine tumor and normal organ doses. Subsequent treatment was then performed with the agent that showed favorable tumor-to-normal organ dose ratios or with ¹⁷⁷Lu-PSMA I&T if the differences in the tumor-to-normal organ dose ratios were similar. ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-rhPSMA-7.3 were prepared in compliance with the German Medicinal Products Act, AMG §13 2b, and after informing the responsible regulatory body (Government of Oberbayern, Germany). The institutional review board of the Technical University of Munich approved the retrospective scientific analysis of the dosimetry data (115/18 S-KK).

Between April 2018 and November 2020, 6 patients agreed to undergo these dosimetric investigations. Patient characteristics are presented in Supplemental Table 1 (supplemental materials are available at http://jnm.snmjournals.org). The approach was based on the rationale of individual selection of the optimal ligand for a specific patient to offer the possibility of benefit from higher tumor uptake, as recent preclinical data indicated (16).

Definitions of Therapeutic Index (TI) and Relative TI (rTI)

To assess the potential antitumor effect in relation to organs at risk of ¹⁷⁷Lu-PSMA I&T versus ¹⁷⁷Lu-rhPSMA-7.3, a TI was calculated. It was defined as the mean radiation dose to tumor lesions divided by the radiation dose to relevant organs at risk. As the kidneys and bone marrow are the most relevant organs, we report the TI for the kidneys and the TI for the bone marrow (4). The respective rTI was defined as the ratio of the TI of ¹⁷⁷Lu-rhPSMA-7.3 to the TI of ¹⁷⁷Lu-PSMA I&T, with a value of greater than 1 indicating a distribution favoring ¹⁷⁷Lu-rhPSMA-7.3.

Pretherapeutic Dosimetry, Image Analysis, and Dosimetric Calculations

The mean applied pretherapeutic activities were 1,066 ± 83 MBq (range, 1,000–1,243 MBq) for ¹⁷⁷Lu-PSMA I&T and 1,012 ± 51 MBq (range, 917–1,083 MBq) for ¹⁷⁷Lu-rhPSMA-7.3. Activity was injected over approximately 1 min and was followed by a saline flush. Specific activities were 47.5 GBq/0.59 μmol for ¹⁷⁷Lu-PSMA I&T and 47.5 GBq/0.61 μmol for ¹⁷⁷Lu-rhPSMA-7.3. The mean time period between application of both agents was 172 h (range, 166–190 h). Whole-body scintigraphy was performed at least 1 h, 4 h, 24 h, 48 h, and 7 d after administration.

Individual patient absorbed doses for the whole body, kidneys, liver, parotid, submandibular, and lacrimal glands, tumor lesions, and red bone marrow were estimated on the basis of the MIRD scheme, as recommended in the European Association of Nuclear Medicine Dosimetry Committee Guidelines. Absorbed organ and tumor doses for each cycle were calculated using OLINDA/EXM (18–20). Details on the regions of interest (ROIs) for scintigraphy and the volume calculations for PET are given in the supplemental data (e.g., Supplemental Table 2).

Statistical Analysis

All continuous data reported are expressed as mean ± SD and range. A nonpaired t test followed by Welch correction was performed to compare means. Statistical analyses were conducted using GraphPad Prism (version 5.0; GraphPad Software).

RESULTS

Qualitative ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-rhPSMA-7.3 Biodistributions on Pretherapeutic Scintigraphy

Physiologic uptake was seen in the lacrimal, parotid, and submandibular glands, kidneys, and small intestine; uptake was less pronounced in the liver and spleen. Uptake in excess of the background was also seen for multiple tumor lesions, with progressive accumulation up to 24–48 h after injection for ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-rhPSMA-7.3 (Fig. 1). Delayed whole-body images (up to 7 d after therapy) exhibited long-term retention of ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-rhPSMA-7.3 in the metastases, with nearly no residual uptake in normal organs.

FIGURE 1.

Examples of ROIs in 1 patient for ¹⁷⁷Lu-PSMA I&T (top) and ¹⁷⁷Lu-rhPSMA-7.3 (bottom).

Pretherapeutic Dosimetry of Normal Organs

The mean whole-body pretherapeutic effective dose for ¹⁷⁷Lu-rhPSMA-7.3 was 0.117 Gy (0.12 ± 0.07 Sv/GBq), and that for ¹⁷⁷Lu-PSMA I&T was 0.054 Gy (0.05 ± 0.03 Sv/GBq). The mean absorbed organ doses for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T were 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq, respectively, for the kidneys; 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq, respectively, for the liver; 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid glands, respectively; 2.10 ± 0.86 and 0.67 ± 0.31 Gy/GBq for the submandibular glands, respectively; and 5.29 ± 2.16 and 1.92 ± 0.80 Gy/GBq for the lacrimal glands, respectively (Supplemental Table 3). Figure 2 and Supplemental Figs. 1 and 2 display mean organ doses, individual organ doses, and individual percentage injected doses.

FIGURE 2.

Mean organ doses (Gy/GBq) for kidneys, liver, parotid, lacrimal, and submandibular (Submand.) glands, and tumor lesions and total-body doses (Sv/GBq) determined with ¹⁷⁷Lu-PSMA I&T (I&T) and ¹⁷⁷Lu-rhPSMA-7.3 (rh) for all patients. Individual patient organ doses are shown in Supplemental Figs. 1–3. RM = red bone marrow. RM* = using an ROI for correction next to the lumbar spine (n = 4); RM** = using an ROI in the thigh (n = 6); ^#Sv/GBq.

Pretherapeutic Dosimetry of Bone Marrow

When ROIs were placed in the thigh regions, red bone marrow absorbed doses were 0.67 ± 0.62 Gy/GBq for ¹⁷⁷Lu-rhPSMA-7.3 and 0.30 ± 0.27 Gy/GBq for ¹⁷⁷Lu-PSMA I&T. Data for bone marrow dosimetry obtained with ROIs next to the lumbar spine for correction are presented in Supplemental Tables 3 and 4.

Pretherapeutic Dosimetry of Tumor Lesions

A total of 21 representative lesions were analyzed (14 bone and 7 lymph node metastases). Mean and individual sizes of individual tumor lesions are given in the supplemental materials and Supplemental Table 2.

The pretherapeutic mean absorbed doses of tumor lesions were 6.44 ± 6.44 Gy/GBq (range, 0.66–29.25 Gy/GBq) for ¹⁷⁷Lu-rhPSMA-7.3 and 2.64 ± 2.24 Gy/GBq (range, 0.38–9.80 Gy/GBq) for ¹⁷⁷Lu-PSMA I&T. The pretherapeutic mean absorbed doses for bone and lymph node metastases were 4.09 ± 2.57 and 11.14 ± 8.83 Gy/GBq, respectively, for ¹⁷⁷Lu-rhPSMA-7.3 and 1.70 ± 1.13 and 4.51 ± 2.69 Gy/GBq, respectively, for ¹⁷⁷Lu-rhPSMA-7.3 (Table 1). Figure 2 and Supplemental Figs. 1–3 display mean tumor doses, individual tumor doses, and individual percentage injected doses.

TABLE 1.

Effective Doses for Tumor and Ratios to Effective Doses for Kidney and Bone Marrow

			177Lu-rhPSMA-7.3 (rh)			177Lu-PSMA I&T (I&T)
Patient	Tumor no.	Tumor site	Tumor dose (mGy/MBq)	TI for kidneys	TI for bone marrow	Tumor dose (mGy/MBq)	TI for kidneys	TI for bone marrow	Ratio of tumor rh to tumor I&T	rTI for kidneys	rTI for bone marrow*
1	1	B	3.00	1.91	3.63	1.31	2.07	3.45	2.30	0.92	1.05
	2	B	1.58	1.01	1.91	0.73	1.16	1.94	2.16	0.87	0.99
2	1	B	4.05	2.33	11.60	1.38	1.71	9.82	2.95	1.36	1.18
	2	B	6.94	3.99	19.90	2.31	2.88	16.51	3.00	1.39	1.21
	3	LN	29.25	16.81	83.81	9.80	12.20	70.00	2.98	1.38	1.20
	4	B	2.81	1.62	8.05	0.88	1.09	6.27	3.20	1.48	1.28
	5	B	1.53	0.88	4.37	0.52	0.65	3.72	2.94	1.35	1.18
3	1	LN	16.15	11.97	43.42	5.15	10.42	35.99	3.14	1.15	1.21
	2	LN	14.00	10.37	37.63	5.93	12.01	41.49	2.36	0.86	0.91
	3	B	1.56	1.16	4.20	0.73	1.47	5.07	2.15	0.79	0.83
4	1	B	2.21	1.24	8.24	0.92	0.97	8.45	2.40	1.28	0.98
	2	LN	3.46	1.94	12.91	1.22	1.28	11.19	2.84	1.52	1.15
5	1	B	6.88	3.23	3.55	2.79	2.96	3.26	2.47	1.09	1.09
	2	B	6.67	3.13	3.44	3.00	3.18	3.51	2.22	0.99	0.98
	3	B	5.92	2.78	3.05	2.69	2.85	3.14	2.20	0.98	0.97
	4	B	9.49	4.46	4.89	4.37	4.63	5.11	2.17	0.96	0.96
	5	B	3.91	1.84	2.02	1.82	1.93	2.13	2.15	0.95	0.95
6	1	B	0.66	0.50	3.38	0.38	0.66	4.00	1.72	0.75	0.85
	2	LN	8.05	6.05	41.28	4.66	8.06	48.54	1.73	0.75	0.85
	3	LN	3.38	2.54	17.32	1.93	3.33	20.06	1.75	0.76	0.86
	4	LN	3.71	2.79	19.03	2.89	5.00	30.10	1.28	0.56	0.63
Mean ± SD for all			6.44 ± 6.44†	3.93 ± 4.07‡	16.08 ± 19.79‡	2.64 ± 2.24	3.83 ± 3.58	15.89 ± 18.28	2.39	1.05	1.01
Mean ± SD for B			4.09 ± 2.57§	2.15 ± 1.17‡	5.87 ± 4.68‡	1.70 ± 1.13	2.02 ± 1.11	5.46 ± 3.76	2.43	1.08	1.03
Mean ± SD for LN			11.14 ± 8.83‡	7.50 ± 5.27‡	36.49 ± 22.49‡	4.51 ± 2.69	7.47 ± 4.03	36.77 ± 17.90	2.30	1.00	0.97

^*Results for red marrow dosimetry using ROI placed in thigh.

^†P = 0.02.

^‡Not significant.

^§P = 0.007.

B = bone; LN = lymph node.

Data for all patients are presented for individual tumor lesions and grouped by tumor lesion type.

TI and rTI

The mean TIs for the kidneys were 3.7 ± 2.2 for ¹⁷⁷Lu-rhPSMA-7.3 and 3.6 ± 2.2 for ¹⁷⁷Lu-PSMA I&T. Intraindividual comparisons of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T revealed a higher TIs for the kidneys in 2 patients for ¹⁷⁷Lu-rhPSMA-7.3 (patient 2: 5.1 vs. 3.7; patient 4: 1.6 vs. 1.1) and in 1 patient for ¹⁷⁷Lu-PSMA I&T (patient 6: 2.9 vs. 4.3). In 3 patients, no clear differences were seen (patient 1: 1.5 vs. 1.6; patient 3: 7.8 vs. 7.9; patient 5: 3.1 vs. 3.1). Consequently, the rTI for the kidneys was greater than 1 in patients 2 and 4 and less than or equal to 1 in all other patients. The individual TIs and the rTIs are shown in Figures 3A and 3B, respectively.

FIGURE 3.

TIs (A) and rTIs (B) for tumor-to-kidney ratio for each individual patient. Values of >1 indicate favorable biodistribution for ¹⁷⁷Lu-rhPSMA-7.3 (rh) compared with ¹⁷⁷Lu-PSMA I&T (I&T) and vice versa. Two patients had favorable distribution of ¹⁷⁷Lu-rhPSMA-7.3, 1 patient had favorable distribution of ¹⁷⁷Lu-PSMA I&T, and in 3 patients no clear preference was observed.

When ROIs in the thigh were used, the mean TIs for the bone marrow were 15.2 ± 10.2 for ¹⁷⁷Lu-rhPSMA-7.3 and 15.1 ± 10.2 for ¹⁷⁷Lu-PSMA I&T. Intraindividual comparisons of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T revealed that ¹⁷⁷Lu-rhPSMA-7.3 showed higher TIs for the bone marrow in 4 patients (patient 1: 2.8 vs. 2.7; patient 2: 25.5 vs. 21.3; patient 3: 28.4 vs. 27.5; patient 4: 10.6 vs. 9.8). In 1 patient, no clear difference was measured (patient 5: 3.4 vs. 3.4), and in another patient, ¹⁷⁷Lu-PSMA I&T showed a higher TI for the bone marrow (patient 6: 20.3 vs. 25.7).

DISCUSSION

We presented data on pretherapeutic radiation dosimetry for normal organs and tumor lesions for ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T in 6 mCRPC patients. Quantitative analyses revealed, on average, an absorbed dose to tumor lesions of ¹⁷⁷Lu-rhPSMA-7.3 that was 2.4 times higher than that of ¹⁷⁷Lu-PSMA I&T. This finding is in line with recent preclinical data demonstrating a 2.6-fold difference (16). However, in our clinical investigation, absorbed doses to normal organs were also 2–3 times higher (e.g., 2.3 for the kidneys, 2.9 for the parotid glands, and 2.2 for the bone marrow). Notably, these relationships substantially differed at the patient level.

Because of controversies about the extrapolation of preclinical evaluations, pretherapeutic clinical dosimetry is important (21). Currently, dosimetry for PSMA ligands focuses on absorbed doses delivered to normal organs, primarily the kidneys but also the salivary glands as the most relevant organs at risk. Despite numerically high absorbed doses to the salivary and parotid glands, clinically relevant toxicity has only been anecdotally reported and has been mainly transient (22). Although red bone marrow dosing is essential, its methodology is prone to errors—for example, as a result of the frequent presence of extensive bone metastases. Nevertheless, bone marrow toxicity even in the presence of extensive osseous metastases is not a frequent side effect (4,23).

rhPSMA ligands belong to a new class of fully theranostic agents (16). They allow the use of radiochemical twins, such as ¹⁹F/¹⁷⁷Lu-rhPSMA or ¹⁸F/^natLu-rhPSMA, for potential pretherapeutic PET-based imaging and subsequent PSMA RLT (24). Recently published promising preclinical data demonstrated that the radiohybrid ¹⁹F/¹⁷⁷Lu-rhPSMA-7.3 is a suitable candidate for clinical translation because of similar clearance kinetics and radiation doses but superior tumor uptake and retention compared with ¹⁷⁷Lu-PSMA I&T (16). Using this approach, our aim was to investigate ¹⁷⁷Lu-rhPSMA-7.3 by comparing it to ¹⁷⁷Lu-PSMA I&T as the established agent for PSMA RLT, allowing us to maximize the absorbed radiation dose to tumor lesions and to minimize the absorbed radiation dose to relevant organs at risk.

When differences in radiation doses to normal organs are investigated, the kidneys are usually regarded as dose-limiting organs at risk. Pretherapeutic kidney doses in our 6 mCRPC patients were 2.3 times higher with ¹⁷⁷Lu-PSMA-7.3 than with ¹⁷⁷Lu-PSMA I&T. Regarding potential radiation damage, currently either 23 Gy with a 5% probability of late kidney damage within 5 y or 28 Gy with a 50% probability of late kidney damage within 5 y is used (25). For ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617, severe kidney toxicity has been described as a side effect in only a few patients (26). However, care must be taken given the limited overall survival of late-stage mCRPC patients. Kabaskal et al. calculated a maximum activity of 32.9 GBq to achieve a 23-Gy kidney dose report for ¹⁷⁷Lu-PSMA-617 using pretherapeutic dosimetry (10). For ¹⁷⁷Lu-rhPSMA-7.3, our mean data would indicate the option to apply approximately 17 GBq on the basis of a mean of 1.65 Gy/GBq. However, this lower activity would achieve similar absorbed tumor doses. It remains to be decided which activity levels and timing of cycles will be pursued in any potential clinical development of ¹⁷⁷Lu-rhPSMA-7.3. Nevertheless, we believe that the presented data might inform potential future study protocols.

Notably, given the results of the VISION trial, bone marrow toxicity is a rare but relevant side effect (4). In our retrospective study, the radiation delivery to the bone marrow was 2.2 times higher for ¹⁷⁷Lu-rhPSMA-7.3. The relative TI of 1.2, integrating absorbed doses to both tumors and bone marrow, suggests only a slight improvement over ¹⁷⁷Lu-PSMA I&T.

However, the calculation of red bone marrow doses is complex when based on scintigraphic images. For example, in 2 of our patients, radiation exposure of the bone marrow was probably overestimated because of the presence of tumor lesions in the ROI. Nevertheless, although important for absolute values, the ratio between ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T was probably less affected. Our results for bone marrow dosimetry showed mean absorbed doses of 0.67 ± 0.62 mGy/MBq for ¹⁷⁷Lu-rhPSMA-7.3 and 0.30 ± 0.27 mGy/MBq for ¹⁷⁷Lu-PSMA I&T. These doses resulted in a favorable tumor-to-bone marrow index in 3 patients. The absolute values were substantially higher than those reported in the literature for ¹⁷⁷Lu-PSMA-617, but the difference can be mainly explained by the different methods (thigh vs. lumbar spine correction) (7,8).

It is important to emphasize that the absorbed dose limits for solid organs are based on conventionally fractionated external-beam therapy and cannot necessarily be directly applied to low-dose-rate radiation (27). Patients without risk factors for kidney disease might tolerate a renal biologic equivalent dose up to 40 Gy, on the basis of experience with radiopeptide treatment of neuroendocrine tumors (28). However, dosimetry is an important but not the only factor for determining the safety of a radionuclide treatment. As observed in a similar setting comparing somatostatin agonist and antagonist treatments, disproportionately higher hematotoxicity was observed with the somatostatin antagonist, with up to 57% of patients experiencing grade 4 hematotoxicity after 2 cycles (29).

High variability of absorbed doses was observed in tumor lesions, similar to data reported for ¹⁷⁷Lu-PSMA I&T (5) and ¹⁷⁷Lu-PSMA-617 (8,30–32). The broad range might be partially attributable to the fact that our patients had only a few lesions. Similar to organ dosimetry, the relationship of the absorbed doses of both ligands is a more reliable parameter than the absolute values. Okamoto et al. and Baum et al. reported absorbed doses between 0.22 and 12.0 Gy/GBq and between 0.02 and 78 Gy/GBq, respectively, for ¹⁷⁷Lu-PSMA I&T (5,33). For ¹⁷⁷Lu-PSMA-617, Violet et al. reported mean absorbed doses of 5.28 Gy/GBq for bone metastases and 3.91 Gy/GBq for lymph node metastases (32).

Integrating all the previously discussed data for organs and tumor lesions, we calculated the TI for the kidneys in all patients (Fig. 3). Ultimately, 2 patients were treated with ¹⁷⁷Lu-rhPSMA-7.3, as pretherapeutic dosimetry indicated a clear advantage. In 1 patient, ¹⁷⁷Lu-PSMA I&T was used, given its clearly favorable profile. In the remaining 3 patients, the TI did not favor either of the 2 PSMA ligands. On the basis of the TI for the bone marrow, 3 patients had a favorable profile for ¹⁷⁷Lu-rhPSMA-7.3 and 3 patients had a favorable profile for ¹⁷⁷Lu-PSMA I&T.

Our analyses warrant some discussion on how the different characteristics of ¹⁷⁷Lu-rhPSMA-7.3 can be exploited. Potential options for a drug development program would be the application of similar activities, as recommended for ¹⁷⁷Lu-PSMA I&T and ¹⁷⁷Lu-PSMA-617, which would lead to higher absorbed tumor doses and potential efficacy (34). This approach could be feasible given the so-far low toxicity profile of ¹⁷⁷Lu-PSMA in general, with reported injected activities of up to 2 doses of 11 GBq of ¹⁷⁷Lu-PSMA-617 (applied within 1 wk) (35). However, long-term toxicity for the kidneys of ¹⁷⁷Lu-PSMA in general is unclear, and even the potential dose limits are controversial. Alternatively, similar tumor and organ doses with a smaller amount of activity and subsequently with a lower cost could be achieved, especially when non–carrier-added ¹⁷⁷Lu is used for treatment (36). In the context of an expected large number of patients to be treated with PSMA RLT in the future, smaller amounts of ¹⁷⁷Lu would also improve practical aspects (e.g., radioactive material program licensing, improved radiation safety for involved medical personnel).

Our retrospective analysis has limitations. First, only a small number of patients could be analyzed. Second, numerous factors can impair the accuracy of PET and planar dosimetry and can lead to a decreased correlation of the 2 modalities. Overlay in planar scintigraphy can lead to an overestimation of the absorbed dose, and further errors can occur for volumetric assessment (8,37). We tried to minimize such errors by adjusting the volume of interest using information from PET for the anatomic configuration of the lesions. However, especially for bone lesions, anatomic delineation can be difficult. Third, our dosimetry analyses for the bone marrow were prone to substantial challenges, as described earlier. As an alternative, we applied an additional method, using correction from tissue adjacent to the tissue in the thigh. In principle, this method is used in clinical dosimetry. However, as discussed earlier, it usually results in higher absorbed doses (less background to be subtracted in the thigh than adjacent to the lumbar spine), and no data are available in the literature to compare it with other PSMA ligands. Fourth, our pretherapeutic dosimetry using 1 GBq of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T might already have achieved some therapeutic effect. Given the higher tumor doses delivered by ¹⁷⁷Lu-rhPSMA-7.3, the dosimetry of subsequent ¹⁷⁷Lu-PSMA I&T might be more affected than the dosimetry of ¹⁷⁷Lu-rhPSMA-7.3 after ¹⁷⁷Lu-PSMA I&T. We tried to minimize this bias by alternating the sequence of pretherapeutic applications.

CONCLUSION

Pretherapeutic clinical dosimetry confirmed preclinical results, with mean absorbed doses for tumors of ¹⁷⁷Lu-rhPSMA-7.3 that were 2–3 times higher than those of ¹⁷⁷Lu-PSMA I&T. Absorbed doses to normal organs increased at different levels, including the bone marrow. The newly introduced TI allowed for individual adjustment of absorbed tumor doses for the kidneys and the bone marrow as organs at risk. For the kidneys, it identified 2 of 6 patients with a clearly favorable biodistribution of ¹⁷⁷Lu-rhPSMA-7.3 compared with ¹⁷⁷Lu-PSMA I&T and a similar profile in 3 of 6 patients. For the bone marrow, a favorable profile was observed in 3 of 6 patients for ¹⁷⁷Lu-rhPSMA-7.3 and in 3 of 6 patients for ¹⁷⁷Lu-PSMA I&T. ¹⁷⁷Lu-rhPSMA-7.3 holds promise for a therapeutic effect similar to that of ¹⁷⁷Lu-PSMA I&T at lower absorbed doses and offers potential economical and radiation safety benefits.

DISCLOSURE

H.-J. Wester, A. Wurzer, and M. Eiber have applied for a patent for rhPSMA. H.-J. Wester is founder, shareholder, and advisory board member of Scintomics GmbH, Fuerstenfeldbruck, Germany. W.A. Weber reports prior consulting activities for Blue Earth Diagnostics Ltd. M. Eiber reports prior consulting activities for Blue Earth Diagnostics Ltd., Novartis, Telix, Progenics, Bayer, Point Biopharma, and Janssen. No other potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Are the biodistribution, dosimetry, and therapeutic efficacy of ¹⁷⁷Lu-rhPSMA-7.3 and ¹⁷⁷Lu-PSMA I&T comparable?

PERTINENT FINDINGS: In mCRPC, pretherapeutic organ and tumor absorbed doses for ¹⁷⁷Lu-rhPSMA-7.3 were higher than those for ¹⁷⁷Lu-PSMA I&T, whereas the TI was equal to the mean for the kidney absorbed dose. Using ¹⁷⁷Lu-rhPSMA-7.3 could lead to the same therapeutic effect without higher nephrotoxicity and with smaller amounts of radioactivity.

IMPLICATIONS FOR PATIENT CARE: Pretherapeutic data indicate higher tumor absorbed doses for ¹⁷⁷Lu-rhPSMA-7.3 in radioligand treatment, a finding that should be explored in prospective clinical studies.