Hematologic safety of ¹⁷⁷Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is associated with high disease-specific morbidity and mortality [1]. Therapeutic options prolonging overall survival are limited to second-generation antiandrogens (enzalutamide and abiraterone), sipuleucel-T and potentially myelotoxic treatments, including taxane-based chemotherapy and bone-seeking ²²³Ra-dichloride [2‐7]. In recent years, radioligand therapy (RLT) directed at the type II transmembrane glycoprotein prostate-specific membrane antigen (PSMA) has been increasingly adopted as a novel treatment for mCRPC. Small-molecule PSMA inhibitors labeled with beta-emitting ¹⁷⁷Lutetium, most notably the Glu-urea-based radioligand ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-DOTAGA-(I-y)fk(Sub-KuE), briefly termed ¹⁷⁷Lu-PSMA-I&T have yielded promising anti-tumoral activity with favorable overall tolerability [8, 9].

Hematological decline is a frequent occurrence in patients with progressive mCRPC and considered a risk factor for poor outcome. Based on evidence derived from peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasias, the risk of myelosuppression has been taken into account as dose-limiting factor also in RLT. While descriptive assessment of myelotoxic events has been included in a number of prospective and retrospective trials [9‐18], their association with potential predisposing factors remains to be elucidated.

Pretreatment factors implicated in the risk of myelosuppression during radionuclide therapy may include preexisting hematologic impairment, previous myelotoxic therapies and bone tumor burden [19]. Irradiation to the bone marrow during RLT can further add to deterioration of hematopoietic function [20]. However, the impact of RLT-specific variables, including administered treatment activity and cumulative activity, has so far not been investigated.

The aim of this study was to examine incidence, severity and reversibility of myelosuppression in patients undergoing RLT with ¹⁷⁷Lu-PSMA-617 in a sizable and heterogenous cohort. Predisposing factors, including previous therapies, disease burden, as well as administered activity per cycle and treatment course, were then analyzed regarding their contribution to new onset hematologic adverse events.

One hundred forty consecutive patients with mCRPC (median age 72 [IQR 67–78] years) met the eligibility criteria for RLT and underwent treatment at our institution. Patient characteristics at baseline are summarized in Table 1. Upon treatment initiation, 109 (78%) patients had low-grade anemia (85 grade 1, 24 grade 2), 13 (9%) leukopenia (10 grade 1, 3 grade 2) and 15 (11%) thrombocytopenia (13 grade 1, 2 grade 2). Two patients with hemoglobin levels slightly below the inclusion threshold (both 7.7 g/dL) were treated after individual consent and lack of therapeutic alternatives. Patients received a total of 497 cycles of ¹⁷⁷Lu-PSMA-617 with a mean treatment activity of 6.9 \(\pm\) 1.3 GBq given in a median of 3 (IQR 2–5) treatment cycles. RLT cycles were administered at intervals of 4–8 weeks, reaching a mean cumulative activity of 24.6 \(\pm\) 15.9 GBq. The median follow-up period was 8 (IQR 4–13) months from the start of treatment.

In the presented retrospective study, 140 patients receiving RLT for mCRPC were assessed for occurrence of hematologic adverse events and the role of contributing factors. Significant (grade ≥ 3) hematologic toxicity occurred in 3.4% (17/497) of all treatment cycles and in 9.3% (13/140) of all patients undergoing RLT. Hematologic adverse events were manageable and most likely to occur in patients with extensive bone tumor burden (disseminated or diffuse, OR: 5.08, 95%CI 1.08–23.86, p = 0.04). Patients with baseline myelosuppression (grade ≥ 2 cytopenia OR: 3.50, 95%CI 1.08–11.32, p = 0.04) or previous taxane-based chemotherapy (OR: 4.62, 95%CI 1.23–17.28, p = 0.02) also had higher odds of experiencing grade ≥ 3 myelosuppression.

Available taxane-based chemotherapeutic agents for progressive mCRPC bear a risk hematotoxicity, especially to white blood cells. The phase 3 TAX 327 trial for docetaxel yielded grade ≥ 3 neutropenia in 32%; the TROPIC trial reported grades ≥ 3 leukopenia in 68% of patients receiving cabazitaxel [3, 4, 25]. Myelosuppression is also a known side effect in radionuclide therapy [26]. Toxic effects to hematopoietic cells are mediated by both blood-driven recirculating ß-irradiation and scatter radiation from bone metastases. Long-standing experience from peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasias (NEN) with ¹⁷⁷Lu-labeled DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE) yielded moderate grade ≥ 3 hematotoxicity rates in the range of 8 to 11.3% [26‐29]. Beyond the emergence of subacute toxicity, myelodysplastic syndrome (MDS) may develop as a rare, but severe long-term sequel after PRRT in 1–2% of all patients treated [26, 30]. Apart from effects attributable to diverging biokinetics, it may be hypothesized that MDS is less likely observed after ¹⁷⁷Lu-PSMA-617 due to shorter survival of patients with mCRPC as compared to NEN.

Initial radioimmunological approaches targeting an extracellular PSMA epitope were limited by high rates of myelotoxicity related to the longer plasma half-life inherent to circulating antibodies [31]. In a phase 2 study with the ¹⁷⁷Lu-labeled monoclonal antibody J591 conducted by Tagawa et al., 47% of all patients developed grade 4 thrombocytopenia necessitating aggressive management and transfusion therapy in 30% of all patients enrolled [32, 33]. Following the advent of the small-molecule ligands ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T multiple studies, predominantly within compassionate use programs have included assessment of hematologic adverse events in heterogeneous mCRPC cohorts. Reported overall incidence rates are summarized in Table 5 [9‐18, 34‐43]. The landmark phase 2 trial conducted by Hofman et al. in 30 patients receiving ¹⁷⁷Lu-PSMA-617 reported grade ≥ 3 anemia, neutropenia and thrombocytopenia in 13%, 37% and 4% [8]. Results from a large retrospective study by Heck et al. in 100 patients receiving 317 cycles of ¹⁷⁷Lu-PSMA I&T indicated lower rates, with grade ≥ 3 anemia, neutropenia and thrombocytopenia in 9%, 6% and 6%, respectively [9]. It has to be acknowledged that comparison of white blood cell toxicity in our study was impeded by the fact that differential blood counts for neutrophils and lymphocytes were not available for analysis in all our patients. Recently, Barber et al. contributed a comparative retrospective study using both ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T in 83 patients previously treated with taxane-based chemotherapy and 84 taxane-naïve controls. Grade ≥ 3 anemia, leukopenia and thrombocytopenia occurred in 8% vs. 1%, 2 vs. 0% and 4% vs. 1% of all study patients [35]. The latter findings indicate an adverse impact of previous taxane-based chemotherapy on subsequent hematotoxcity during RLT, as described in our cohort. In the most recent randomized, multicentric phase 2 trial by Hofman et al. (TheraP, ANZUP 1603) previous treatment with docetaxel was an inclusion criterion. Here, grade ≥ 3 anemia, leukopenia and thrombocytopenia occurred in 8%, 1% and 11% of 98 patients receiving ¹⁷⁷Lu-PSMA-617, as compared to 8%, 1% and 0% in the standard-of-care arm (n = 85) treated with cabazitaxel [44].

We report new onset grade ≥ 3 anemia, leukopenia and thrombopenia in 7% (10/140), 4% (5/140) and 4% (6/140) of patients, respectively. Despite delimiting pre-existing cytopenia from therapy-emergent toxicity, differentiation of hematologic decline due to disease progression from true therapy-emergent toxicity remains challenging due to frequently overlapping phenomena. For a conservative estimate, we considered all new onset grade ≥ 3 toxicities in our analysis, regardless of disease progression being a likely contributing factor in a number of cases. Overall, our results appear well in line with data from the foregoing retrospective and prospective studies, taking into account the significant portion of patients with extensive tumor burden and baseline low-grade myelosuppression in the examined cohort.

Our study points toward an influence of predisposing factors on emergence of grade ≥ 3 hematologic adverse events, including taxane-based chemotherapy and initial grade 2 cytopenia. This may be explained by DNA damage conferred by cytotoxic agents [45]. In addition, sequential failure on multiple systemic treatments preceding RLT puts patients at higher odds of developing hematologic decline through disease progression over time. In their post hoc hematologic safety analysis of the ALSYMPCA trial, Vogelzang et al. report both previous taxane-based chemotherapy with docetaxel and baseline cytopenia (anemia and thrombocytopenia) to be associated with grade ≥ 2 thrombocytopenia in mCRPC patients undergoing ²²³Ra-dichloride [19]. Interestingly, the placebo arm also contained relevant rates of new onset toxicity with grade ≥ 3 anemia, neutropenia and thrombocytopenia in 14%, 1% and 3%, underlining the notion that the natural course of mCRPC itself is linked to significant deterioration of bone marrow reserve. In further accordance with our observations in RLT, increased tumor burden (defined as ≥ 6 metastases) was also a predictive factor for hematotoxicity in mCRPC patients receiving ²²³Ra-dichloride.

In our cohort, a slight trend toward grade ≥ 3 hematologic toxicities, especially thrombocytopenia, was observed with decreasing eGFR values. This effect has been described also in PRRT and attributed to decreased plasma clearance of recirculating radionuclides in chronic kidney disease [28, 46].

Cumulative activity and individual treatment activity play a distinct role in defining appropriate regimens for RLT, and various RLT-schemes have been put forth. Rathke et al. clustered 40 patients into treatment groups receiving 4, 6, 7.4 or 9.3 GBq of ¹⁷⁷Lu-PSMA-617 reporting comparable safety and efficacy, while pointing out a lower mean platelet count in the 10 patients having received 9.3 GBq [39]. Our treatment routine allowed for individual dose adaptation and yielded no correlation between higher treatment activities or high cumulative activities with increased rates of hematologic adverse events. Potential bias must be considered when interpreting the bivariate association of treatment activity and hematotoxic events since myelosuppression was one reason for individual dose de-escalation.

A major limitation to the conducted analysis is undoubtably its retrospective design. The presented patient population is highly heterogenous and may differ from previously reported series, taking into account that both a fraction of patients omitting prior chemotherapy after interdisciplinary counseling and a considerable number of patients with wide-spread bone tumor burden were included in our analysis. Prospective phase 3 data are much anticipated, with results from the VISION trial expected in near future [47].

Our findings suggest that repeated cycles of RLT with ¹⁷⁷Lu-PSMA-617 can be carried out at acceptable rates of myelosuppression with cytopenia being most frequently reversible, especially in earlier phases of disease progression. High bone tumor burden, previous taxane-based chemotherapy and initial hematologic decline are possible risk factors for developing significant new onset hematologic adverse events. Administered activity per cycle and cumulative activity had in turn no significant impact. These results call for further refining individualized treatment based on given risk factors for hematologic toxicity.