Background: Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with ¹⁷⁷Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically. Methods: RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 $$\pm$$± 1.3 GBq ¹⁷⁷Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 $$\pm$$± 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0. Results: 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%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08–11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08–23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23–17.28, p = 0.02), while treatment with ²²³Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29). Conclusion: Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous ²²³Ra-dichloride treatment show no significant contribution to incidence rates.

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.

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with ¹⁷⁷Lutetium (¹⁷⁷Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. ⁶⁸Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4–6 weeks after the second cycle. Molecular imaging-based response using SUV_peak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9–10.1) months. In univariate analysis, responders showing partial remission (PR_PSA and PR_TLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUV_peak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with ⁶⁸Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality.

Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [⁶⁸Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2–6) RLT cycles. Maximum and mean standardized uptake values (SUV_max, SUV_mean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7–17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUV_max decline or falling below the blood pool uptake were considered responsive; ≥30% SUV_max increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUV_max, SUV_mean, and TLR values were associated with lesion response by a moderate but significant correlation (r_s = 0.33, p < 0.001, r_s = 0.32, p < 0.001, and r_s = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUV_max, SUV_mean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [⁶⁸Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [¹⁷⁷Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

Bone-seeking ²²³Radium-dichloride (²²³Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with ¹⁷⁷Lutetium-PSMA-617 (¹⁷⁷Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in patients with progressive bone involvement under treatment with ²²³Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started ¹⁷⁷Lu-PSMA-617 within 8 weeks after the last ²²³Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of ²²³Ra and a median of 4 (IQR 2–7) cycles ¹⁷⁷Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first ¹⁷⁷Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of ¹⁷⁷Lu-PSMA-617 after failing ²²³Ra is effective with an acceptable toxicity profile.

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [¹⁷⁷Lu]Lu-PSMA- (¹⁷⁷Lu-PSMA) or [²²⁵Ac]Ac-PSMA-radioligand treatment (²²⁵Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. Methods: A retrospective study was performed in patients who received ¹⁷⁷Lu-PSMA and/or ²²⁵Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. Results: In total, 20 patients were included of which 18 patients received ¹⁷⁷Lu-PSMA radioligand and two patients received tandem treatment with both ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq ¹⁷⁷Lu-PSMA per cycle (interquartile range (IQR) 5.2–7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1–2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received ²²⁵Ac-PSMA developed grade 3–4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09–19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.