Extended therapy with [177Lu]Lu-PSMA-617 in responding patients with high-volume metastatic castration-resistant prostate cancer

Purpose The currently used scheme for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC) consists of 4–6 cycles of 6.0–7.4 GBq [177Lu]Lu-PSMA-617 each. This standard treatment scheme has proved safe and effective resulting in objective response in most patients with no significant toxicity. Many patients, however, show high-volume residual tumor burden after the sixth cycle and may benefit from treatment continuation. Extended treatment with additional cycles has been withheld due to concerns on potential increased toxicity. Methods Twenty-six patients with high-volume residual tumor burden (according to CHAARTED) after standard RLT with [177Lu]Lu-PSMA-617 and no alternative treatment option received additional RLT cycles reaching a median of 10 (range 7–16) cycles with a mean activity of 7.4 ± 0.9 GBq per cycle. Response assessment with [68Ga]Ga-PSMA-11 PET/CT was done every 2–3 cycles or if disease progression was clinically suspected or based on change in PSA value (according to the PCWG3 criteria). Toxicity was measured using routine blood work up including blood counts, liver and renal function, and was graded according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. Results Further PSA decline of 33 ± 28% during the extended treatment was observed in 21/26 (81%) patients, whereas 5/26 (19%) patients showed a PSA increase; correspondingly in 11/21 patients with an initial response (PR or SD) to extended cycles, treatment was discontinued due to progressive disease, whereas six (23%) patients achieved low-volume residual disease. Two (8%) patients died without showing progression, and two (8%) patients are still under therapy. The median progression-free survival was 19 (95% CI: 15–23) months, and the overall survival was 29 (95% CI: 18–40) months. Grade ≥ 3 hematological toxicities occurred in 4/26 (15%) patients during treatment extension, and nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient during the follow-up. Conclusion Extended radioligand therapy is a feasible treatment option in patients with high-volume residual tumor after the completion of standard treatment with six cycles of [177Lu]Lu-PSMA-617. Improved survival and the acceptable safety profile warrant further investigation of the concept of additional cycles in selected patients.


Background
Several systemic treatment options exist for patients with metastatic castration-resistant prostate cancer (mCRPC), predominantly including taxane-based chemotherapies (e.g., docetaxel and cabazitaxel) and new-generation antiandrogen drugs (e.g., enzalutamide and abiraterone). In more recent years, radioligand therapy (RLT) has been introduced for mCRPC patients ineligible for or refractory to other treatment strategies [1]. For this purpose, a selective radiolabeled ligand is used targeting prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein avidly expressed on the surface of prostate cancer cells [2,3]. [ 177 Lu]lutetium is considered the suitable radioisotope for RLT due to its favorable physical characteristics such as its long half-life and short range of emitted medium-energy beta particles.
[ 177 Lu]Lu-PSMA-617 is the most widely used compound for PSMA-targeted RLT with promising antitumor activity and low toxicity.
Initial experiences with 1-3 cycles of 6 GBq [ 177 Lu]Lu-PSMA-617 ([ 177 Lu]Lu-PSMA RLT) showed the therapeutic potential of RLT [4,5]. Subsequent investigations were performed with up to six cycles, demonstrating encouraging results with low toxicity. The current standard treatment scheme consisting of 4-6 cycles of 6-8 GBq [ 177 Lu] Lu-PSMA-617 per cycle proved safe and very effective in the randomized VISION phase III trial, prolonging imagingbased progression [6,7]. Responders, however, frequently show relevant remaining tumor burden after completion of standard [ 177 Lu]Lu-PSMA RLT with six cycles. Exhausting treatment alternatives, these patients may benefit from treatment continuation while being exposed to a tolerable risk of treatment-related hematological or renal adverse events. Few studies included patients receiving more than six cycles [ 177 Lu]Lu-PSMA RLT in a re-treatment context, but the safety of continued [ 177 Lu]Lu-PSMA RLT with more than six cycles has been addressed in only one patient group aiming for complete response [8][9][10][11].
This retrospective study assesses the feasibility of extended RLT in patients showing high-volume disease after six cycles of [ 177 Lu]Lu-PSMA-617. Treatment continued until progression, significant impairment of bone marrow or renal function, or achieving low-volume residual disease not necessitating further [ 177 Lu]Lu-PSMA RLT cycles.

Patients
We retrospectively analyzed 26

Radioligand therapy with [ 177 Lu]Lu-PSMA-617
[ 177 Lu]Lu-PSMA RLT was performed as inpatient procedure at the nuclear medicine therapy ward every 6-8 weeks with an intended activity of 7.4 GBq per cycle. ABX (Advanced Biochemical Compounds GmbH, Radeberg, Germany) provided the PSMA-617 ligand which was labeled in-house with [ 177 Lu]LuCl 3 (ITM Isotopen Technologien München AG, Garching/Munich, Germany) as described in detail previously [13,14]. Salivary glands were cooled with ice packages for 2 h beginning 30 min before the administration to support xerostomia limitation. [ 177 Lu]Lu-PSMA-617 was administered intravenously in 30-60 s preceded and followed by the infusion of 1000 mL sodium chloride 0.9% solution. Renal dosimetry was conducted using planar whole-body scintigraphy and single-photon emission computerized tomography (SPECT) performed at 24 h, 48 h, and 72 h p.i. Patients' renal masses were determined using CT images.

Response and toxicity assessment
PSMA-based imaging response was assessed after every 2-3 cycles or if disease progression was suspected using prostate-specific antigen (PSA) as a tumor marker. The international consensus on [ 68 Ga]Ga-PSMA-11 PET/CT imaging response assessment was used for evaluation [15]: partial response (PR, reduction of uptake and tumor PET volume by > 30%), stable disease (SD, uptake and tumor PET volume ± ≤ 30%; no new lesions), and progression (PD, appearance of > 2 new lesions or uptake or tumor PET volume ≥ 30% increased). PSA progression was defined according to the PCWG3 criteria as ≥ 25% increase exceeding 2 ng/mL, confirmed by a second measurement ≥ 3 weeks apart [16].
Hematological (Hb, WBC, and Plt) and renal (eGFR) toxicity evaluation was performed through a blood workup routine at baseline, prior to each therapy cycle, 2-4 weeks after each cycle, and in 6-12-week intervals throughout follow-up. Severity of adverse events was graded based on Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) with grade ≥ 3 toxicities considered significant. Mouth dryness was evaluated at every [ 177 Lu] Lu-PSMA RLT cycle using a modified, self-reported eightitem xerostomia questionnaire [17]. The visual analog scale (VAS; ranging from 0 to 10) was assessed at baseline and at each treatment cycle and used to evaluate the pain level. The ECOG scale was used to assess the patients' performance status.

Statistical analysis
Statistical analyses were performed using the SPSS software (IBM SPSS Statistics 28.0, Armonk, NY, USA). GraphPad Prism version 9.1.1 (GraphPad Software, San Diego, CA, USA) was used to plot graphs. The significance level was set two-sided at p < 0.05. The paired sample t-test was used to compare intraindividual changes in continuous biochemical parameters. Imaging-based progression-free survival (PFS) was defined as the time interval from [ 177 Lu]Lu-PSMA RLT initiation to the date of the first progression, or death, if no imaging-based progression occurred. Overall survival (OS) was defined as the time from treatment initiation to death from any cause; censoring was done if the patient was alive at the time of analysis. PFS and OS were determined using the Kaplan-Meier method (log-rank testing).

Response and survival
Twenty-six patients who responded to six cycles RLT with [ 177 Lu]Lu-PSMA-617 received a median of 4 (IQR 2-6) cycles during extended [ 177 Lu]Lu-PSMA RLT reaching 10 (range 7-16) cycles and a cumulative activity of 75.0 ± 19.1 GBq. In 5/26 (19%) patients, PSA increased despite 1 to 2 additional cycles and disease progression was confirmed on [ 68 Ga]Ga-PSMA-11 PET/CT imaging, leading to treatment termination. In the remaining 21/26 patients showing objective response in [ 68 Ga]Ga-PSMA-11 PET/ CT after six cycles, a further PSA decline of 33 ± 28% was observed after initiation of extended treatment, corresponding to an imaging-based partial response (PR) in 10 patients and stable disease (SD) in 11 patients. Six (23%) patients continued treatment until achieving low-volume disease (n = 5, Fig. 1) or insufficient PSMA expression in remaining tumor lesions (n = 1, Fig. 2). In 11 (42%) patients with initial response (PR + SD) to extended [ 177 Lu]Lu-PSMA RLT, progression after subsequent cycles resulted in treatment discontinuation (Fig. 3). Two (8%) patients are still under treatment, and two (8%) patients died without showing disease progression or significant toxicity (Fig. 4). No treatment-induced clinical deterioration or death was recorded. Performance status improved in all nine patients with an uncontrolled pain state (VAS ≥ 4, ECOG 2; Table 1)
Mean administered activity was 7.4 ± 0.9 GBq per cycle, and mean renal absorbed dose was 0.54 ± 0.22 Gy/ GBq resulting in a mean cumulative administered activity of 75.0 ± 19.1 GBq and absorbed total renal dose of 39.7 ± 15.3 Gy. Correlation of cumulative administered activity and cumulative absorbed renal dose up to each cycle is shown in Fig. 7 (r = 0.847, p < 0.001). Mean renal absorbed dose per administered activity increased from 0.47 ± 0.21 GBq/Gy during the first 6 cycles to 0.78 ± 0.13 Gy/GBq after additional cycles (p = 0.012) resulting in cumulative renal absorbed dose of 22.3 ± 10.3 Gy during standard treatment and 17.4 ± 11.3 Gy during additional 4 (IQR 2-6) cycles. A patient example with a cumulative administered activity of 56.4 GBq resulting in a cumulative absorbed renal dose of 14.5 Gy is presented in Fig. 8.
Mean eGFR levels changed from 85.3 ± 18.9 mL/ min/1.73 m 2 to 80.6 ± 16.7 mL/min/1.73m 2 after the 6 th cycle (p = 0.025) and to 65.8 ± 19 mL/min/1.73 m 2 after extended [ 177 Lu]Lu-PSMA RLT at the last follow-up (p = 0.002; Fig. 9). Mean yearly change of eGFR in all patients was − 10.3 ± 8.5 mL/min/1.73m 2 /year. Cumulative absorbed renal dose of > 40 Gy was not significantly associated with a more prominent eGFR reduction per year (− 9 ± 9.5 vs. − 11.5 ± 7.5; p = 0.462) as shown in Fig. 10. Significant nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient 2 months after discontinuation of the extended [ 177 Lu]Lu-PSMA RLT after having received 12 cycles (Fig. 11). No significant xerostomia was reported, but 6/26 (23%) patients developed xerostomia of grades 1 and 2 during the extended treatment and after a median of 10 (IQR 7-12) cycles. A summary of the adverse events is shown in Table 3.     ]Lu-PSMA-I&T, or both was applied, aiming for a complete response (CR). Further PSA decline was seen in 13/26 (50%) patients. Two patients with biochemical CR showed imaging-based CR with no more PSMA-expressing lesions during the additional treatment period. A PFS of 15 months could be reached, but OS was not reported [8].
In patients with metastatic prostate cancer, high-volume disease according to CHAARTED (i.e., hepatic or multifocal bone involvement) is associated with poor prognosis [12]. This negative impact on survival has also been observed in the context of [ 177 Lu]Lu-PSMA RLT using the standard scheme has been proved safe with a low toxicity profile [6]. An increase in cumulative administered activity raises concerns regarding the safety of the treatment. Kidneys along with bone marrow are considered the main dose-limiting organs in patients undergoing [ 177 Lu]Lu-PSMA RLT. In contrast to bone marrow suppression, treatment-induced renal function impairment may become clinically evident months after [ 177 Lu]Lu-PSMA RLT initiation [22][23][24][25][26]. As a result, in patients with a life expectancy of more than 1 year, the cumulative kidney-absorbed dose may only exceed 40 Gy after careful individual benefit-to-risk evaluation [1]. Therefore, in our study, only patients with high total tumor volume and no other promising therapeutic option were selected for extended [ 177 Lu]Lu-PSMA RLT. The mean cumulative kidney-absorbed dose was 39.7 ± 15.3 Gy, and 13/26 (50%) patients received > 40 Gy. Renal-absorbed dose per administered activity (0.54 ± 0.22 Gy/GBq) in our study is in line with the reported values in the literature, most probably due to the high tumor burden and evident tumor sink effect at baseline in our patients (Fig. 9) [1,27]. Only 1/26 (3.8%) patient treated with a cumulated administered activity of 100.4 GBq resulting in a cumulative kidney-absorbed dose of 63.3 Gy developed significant kidney toxicity (grade 3) 18 months after the treatment initiation (Fig. 8). In the phase III VISION trial, grade 3 to 5 renal effects were observed in 3.4% after a median cumulative dose of 37.5 GBq (range, 7-48.3) and a follow-up of 20.9 months [6]. In the study by Derlin et al., no patient showed significant hematological or kidney toxicity (≥ grade 3) and only one patient discontinued [ 177 Lu]Lu-PSMA RLT because of aggravating grade 2 nephrotoxicity; the cumulative kidney-absorbed dose was not reported [8]. In the phase III VISION trial, hematological adverse events (grade ≥ 3) including anemia, leukopenia, and thrombocytopenia occurred in 12.9%, 2.5%, and 7.9%, respectively [6]. In a retrospective study on 140 patients analyzing a total of 497 cycles of [ 177 Lu]Lu-PSMA-617, significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%), and thrombocytopenia in 6 (4.3%) [28]. Observation of significant hematological toxicity in 4/26 (15%) patients in our study supports the established favorable hematological safety profile of [ 177 Lu]Lu-PSMA RLT even after high cumulative activities. Furthermore, the presence of progressive disease in 3 of these 4 patients suggested that significant toxicity may be at least partly attributed to tumor-induced bone marrow impairment [29].
There are some limitations in our study. The small sample size, hampering in-depth statistical analyses, and the retrospective nature, limiting the comparability with   Funding Open Access funding enabled and organized by Projekt DEAL.

Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations
Ethical approval All procedures performed were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients gave written informed consent prior to each therapy cycle, and retrospective data analysis was approved by the ethics committee of Goethe University Frankfurt (approval number: 310/18).