Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study

Prostate cancer is the most common non-skin cancer in the world with over 1.3 million patients diagnosed every year, of which the majority receive surgery or external beam radiotherapy (EBRT) as a curative treatment option (1, 2). However, 20% to 40% of these patients will develop disease recurrence, which is generally revealed by rising serum PSA levels (3). If salvage surgery or EBRT is insufficient to control disease progression, androgen deprivation therapy (ADT) is generally offered, with early initiation in patients with high PSA velocity (e.g., PSA doubling time <6 months; ref. 3).

Despite favorable responses to ADT and novel drug combinations, there is an increasing interest in metastasis-directed therapies (MDT) for low-volume metastatic (i.e., oligometastatic) disease, primarily to postpone relevant ADT-related side-effects (e.g., cardiovascular disease, osteoporosis, fatigue, loss of libido, depression, hot flashes, and weight gain) and thus preserve quality of life for as long as possible (4–9). The STOMP trial offering stereotactic EBRT to very low-volume metastatic hormone-sensitive prostate cancer (mHSPC) observed minimal treatment-related toxicity. Moreover, Ost and colleagues recently reported a five-year ADT-free survival of 34% in the EBRT group compared with 8% in the surveillance group [HR, 0.57; 80% confidence interval (CI): 0.38–0.84; log-rank P = 0.06; refs. 4, 10]. However, MDT with surgery or EBRT is limited by previous interventions and to particular anatomic regions. Thus, there is an unmet need for treatment options in early-stage patients to control recurrent tumor progression while preserving quality of life.

In recent years, [¹⁷⁷Lu]Lu-PSMA-617 radioligand treatment (¹⁷⁷Lu-PSMA) is increasingly applied to patients with end-stage metastatic castrate-resistant prostate cancer (mCRPC) with encouraging responses and tolerable side effects (11–13). This has resulted in an international registration study for use of ¹⁷⁷Lu-PSMA in patients with mCRPC (NCT03511664). However, to date, there are no prospective studies published on patients with prostate cancer undergoing ¹⁷⁷Lu-PSMA in the hormone-sensitive setting or even with low-volume metastatic disease. It is anticipated that ¹⁷⁷Lu-PSMA could also be effective in low-volume metastatic disease with high uptake of radioligands in small lesions resulting in high local radiation doses (14–16). Hence, we aimed to investigate the toxicity, radiation doses, and treatment effect of ¹⁷⁷Lu-PSMA in patients with low-volume mHSPC.

Males (age >50 years) with histologic proven prostate cancer and progressive disease after local therapy (PSA >0.2 μg/L), with a PSA doubling time of <6 months and no curable treatment options (e.g., surgery or EBRT) left were eligible for this trial. In addition, only low-volume disease (≥1 but ≤10 positive lesions) on [⁶⁸Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) with tumor PSMA uptake higher than liver PSMA uptake were included. Temporarily ADT adjuvant to EBRT in the curative setting was allowed; however, this must have been discontinued >3 months prior to inclusion. Normal renal and bone marrow functions were required (MDRD-GFR ≥60 mL/minute, white blood cell count >3.5 × 10⁹/L, platelet count >150 × 10⁹/L, and hemoglobin >6 mmol/L). Patients with visceral metastases were excluded. All inclusion and exclusion criteria are added in the Supplementary Data.

The study was approved by the Medical Review Ethics Committee Region Arnhem-Nijmegen (NL62774.091.17) and was registered on clinicaltrials.gov (NCT03828838). All subjects provided written informed consent before study entry. The trial was done in accordance to the principles of Good Clinical Practice and the Declaration of Helsinki.

During clinical workup, patients underwent PSMA-PET imaging to evaluate PSMA-positive tumor lesions. The PSMA-PET was repeated 1 week prior to the second cycle of ¹⁷⁷Lu-PSMA and 3 and 6 months after the second administration. PSMA-PET was executed under the protocol as described previously (17). All images were reviewed by board-certified nuclear medicine physicians with over 5 years of experience. The radiolabeling of ¹⁷⁷Lu-PSMA-617 is described in the Supplementary Material.

The first cycle of ¹⁷⁷Lu-PSMA consisted of 3 GBq, followed by a second cycle with 3–6 GBq after 7–9 weeks. Thus, the second cycle could be adjusted in case of unfavorable dosimetry results or toxicity. ¹⁷⁷Lu-PSMA was administered by slow intravenous injection over 2–5 minutes. Patients were advised to have adequate oral fluid intake next to a NaCl 0.9% infusion of 2 L per 24 hours. No specific actions were taken to prevent xerostomia. After each cycle, single-photon emission CT/CT (SPECT/CT) was acquired approximately 1, 24, 48, 72, and 168 hours postinjection to perform 3D dosimetry, according to the MIRD scheme (18). For SPECT/CT imaging a Siemens Symbia T16 or Intevo Bold gamma camera was used with a 128 × 128 matrix over 3 bed positions at each time point (including head/neck, abdomen, and pelvis region). The energy window was set at 20% around 208 keV with a lower scatter window of 20% around 170 keV. The SPECTs were reconstructed with a 3D-OSEM algorithm (6 iterations and 16 subsets) with CT-based attenuation and scatter correction (Siemens Flash-3D software). Blood was drawn at 5, 30, 60, 120, and 180 minutes and 24, 48, 72, and 168 hours postinjection to perform blood dosimetry (19). During these same time points vital signs were recorded (blood pressure, heart rate, and temperature).

After administration of ¹⁷⁷Lu-PSMA, patients were monitored weekly at the outpatient clinic until 12 weeks after cycle two and at the end of the study (EOS; 24 weeks after cycle two), to evaluate tolerability, vital signs, and adverse events. Blood for hematology, chemistry, and PSA was drawn weekly to monitor toxicity and response. Quality-of-life questionnaires (EORTC-QLQ-C30) were filled in before and monthly after the first ¹⁷⁷Lu-PSMA injection, until three months after cycle 2. An end-of-study quality-of-life questionnaire was filled in 24 weeks after cycle two. The Supplementary Material includes a study flowchart.

The primary aim of this study was to evaluate the toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.03) and radiation doses to the target lesions and organs at risk. Secondary outcomes were patient-reported quality of life using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30; ref. 20), ADT-free survival, best PSA response from baseline according to Prostate Cancer Working Group 3 (PCWG3) criteria, and imaging response following RECIST 1.1 and the consensus statements on PSMA-PET/CT response assessment criteria in prostate cancer (21, 22).

Because of the explorative nature of this study, no sample size calculations were performed. All data was managed according to GCP requirements using EPIC Software and CastorEDC (https://www.castoredc.com/). Dose calculations to tumor and organs at risk were performed by Hermes Medical Solutions dosimetry software (v2.0), using organ-based dosimetry and cubic or spherical tumor volumes. Data was analyzed by Graphpad Prism version 5.03 and R studio version 1.1.463.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The study protocol was approved by the Medical Review Ethics Committee Arnhem-Nijmegen, the Netherlands (NL62774.091.17). All study participants provided informed consent before study entry.

Between September 1, 2018 and September 23, 2019, 12 patients were screened; 10 of these patients were found eligible. Two patients were found ineligible as they exceeded the maximum allowed tumor volume (>10 metastases). All 10 patients received two cycles of ¹⁷⁷Lu-PSMA. Baseline patient characteristics and administered dose of ¹⁷⁷Lu-PSMA are summarized in Fig. 1. All patients underwent prior local treatment for their prostate cancer with either surgery and/or EBRT. None of the patients received ADT within one year before study inclusion.

All injections of ¹⁷⁷Lu-PSMA were well tolerated (see Table 1). No significant changes were observed in temperature, blood pressure, or heart rate following injection. Seven of the 10 patients developed grade I–II fatigue (with only 1 patient grade II fatigue) after injection which resolved within 2–4 weeks. Two of 10 patients (patient #8 and #9) reported a brief grade I xerostomia after treatment injection. Twelve weeks after cycle two and at EOS, none of the patients reported xerostomia or lacrimal gland toxicity. Patient #2 had a minor rash at the injection site which disappeared without interventions within three days, which was deemed to be most likely related to the adhesive band-aid and not to ¹⁷⁷Lu-PSMA. Patient #4, who had pain at baseline originating from bone metastases, reported brief pain increment following both cycles, with all pain finally disappearing four weeks after cycle two. At 21 weeks following cycle 2, he started ADT due to recurrence of pain progression.

No treatment-related laboratory (hematology, kidney, or liver function) adverse events were observed in any of the 10 patients during the weekly blood evaluation. No major changes were observed in the quality of life of the patients pre- and posttreatment (Fig. 2). The Supplementary Data provides a detailed table of the completed EORTC-QLQ-C30 questionnaires.

¹⁷⁷Lu-PSMA was rapidly eliminated from the blood with >90% and >99% excreted within approximately 24 and 48 hours, respectively. According to the dose calculations, the salivary glands, kidneys, liver, and bone marrow were not at risk with a median total organ dose of 3.4 Gy (range 1.2–5.9 Gy), 4.3 Gy (range 3.1–6.1 Gy), 0.8 Gy (range 0.6–1.1 Gy), and 0.15 Gy (range 0.1–0.2 Gy), respectively. All target lesions had a higher ¹⁷⁷Lu-PSMA uptake compared with the healthy organs with a median dose of 12.7 Gy (range 4.6–48.7 Gy). All doses in Gy/GBq to the organs at risk and target lesions are specified in the Supplementary Material.

All 10 patients showed altered PSA kinetics as shown in Fig. 3. At EOS, 5 patients had response of serum PSA >50% (patients #1, #3, #5, #8, and #9), of which 1 patient had an undetectable PSA (patient #8). Two patients remained stable in PSA (patients #6 and #10) and 3 patients had PSA progression compared with the baseline measurement (patients #2, #4, and #7). In 3 patients, the PSA was still decreasing at EOS (patients #5, #8, and # 9), whereas in 6 patients (patients #1, #2, #3, #4, #7, and #10) the PSA had started rising again. After the first treatment injection, 8 patients (patients #1–3, #6, #7, #9, and #10) had a brief surge in PSA, which declined after a maximum of 5 weeks.

At the end of the study, 6 patients still showed a radiologic response on PSMA-PET imaging and had a stable, partial, or complete response on PSMA-PET, whereas 4 patients had progressive disease (Table 2). The PSMA-PET images of the best responding patients in PSA (patients #1, #8, and #9) are presented in Fig. 4. Lymph node metastases appeared to have a better response on ¹⁷⁷Lu-PSMA compared with bone metastases. Hence, patients (#1, #3, #5, #6, #8, and #9) with solely lymph node metastases had a better response compared with patients (#2, #4, #7, and #10) who also had bone metastases. The Supplementary Data provides a detailed description of all observed metastases, including the size of soft-tissue metastases and SUV_max of all tumors as well as the SUV_mean of the salivary glands and liver.

Asymptomatic patients with low-volume mHSPC are increasingly seeking alternative therapies to defer from ADT-related side effects with negative impact on quality of life (4, 6–9). Hence, a growing number of studies are addressing treatment-related side effects as important trial outcomes (4, 6, 23, 24). Since the development of novel radioligands for PET imaging, salvage surgery or EBRT became an optional therapeutic approach in selected patients with low-volume mHSPC (3, 25, 26). However, not all patients are eligible for these treatments because of tumor location(s) and/or prior therapies. This raises the question whether these early-stage patients can benefit from therapeutic radioligands such as ¹⁷⁷Lu-PSMA.

This study prospectively evaluated ¹⁷⁷Lu-PSMA for the first time in low-volume mHSPCs and observed safety and tolerability in 10 patients. During the study, there were no grade III–IV treatment-related toxicities. Even the observed grade I–II toxicities (e.g., fatigue) subsided within a few weeks. Importantly, only 2 patients reported (very) mild xerostomia, which resolved spontaneously within 1 month after treatment. At the end of the study, none of the patients reported xerostomia or lacrimal gland toxicity. No liver, kidney, or bone marrow toxicity was seen during the weekly blood evaluations.

The outcomes regarding toxicity and quality of life are in concordance with the results from recent prospective trials as well as retrospective data from global compassionate-use programs, considering the poor health of the heavily pretreated patients with mCRPC in those studies (11–13, 27). We administered two cycles containing 3 and approximately 6 GBq ¹⁷⁷Lu-PSMA with 8 weeks in between. This is a relatively low total amount of activity compared with the current standard protocol in end-stage patients with 4–6 cycles and 7.4 GBq per administration (11). The minimal observed toxicity may also be related to the low administered total activity. However, according to the dosimetry results of this study, a higher amount of activity should be safe and is therefore feasible.

After each treatment cycle, a comprehensive 3-D dosimetry protocol was carried out to calculate the delivered doses to the tumor(s) and the organs at risk, including blood collections to evaluate bone marrow dose. This state-of-the-art dosimetry protocol precluded the need for a dose-escalation study. We observed that the tumor target lesions (median 12.7 Gy; range 4.6–48.7 Gy) received a 4–6 times higher radiation dose compared with the kidneys and salivary glands, being the critical dose-limiting organs. The salivary glands received a median cumulative dose of 3.4 Gy (range 1.2–5.9 Gy), which was well below the reported organ threshold dose of 35 Gy (28). This threshold, however, relates to EBRT because the organ limitations for ¹⁷⁷Lu-PSMA are yet unresolved. This also applies to the kidneys (radiation dose in this study: median 4.3 Gy; range 3.1–6.1 Gy), which has an organ limitation dose of 40 Gy according to the recent ¹⁷⁷Lu-PSMA guideline (28). The dosimetry outcomes in this study are comparable with the results in patients with high-volume mCRPC implying that the sink-effect with unfavorable radioligand distribution to the organs at risk in low-volume disease is of less concern than anticipated (29–31). Nonetheless, long-term toxicities, which could develop over time, need evaluation in following studies.

In accordance to the inclusion criteria, all patients had a PSA doubling time < 6 months prior to the study and showed stabilization of the PSA velocity after two cycles as seen in Fig. 3. Five of the 10 patients showed a PSA decline >50%. At the end of the study, PSA was still decreasing in 3 patients, of which 1 patient had a biochemical complete response. The PSA responses observed in this study are similar to those reported by Ost and colleagues after salvage EBRT (4). Eight of 10 patients had a brief surge in PSA after the first therapeutic injection of ¹⁷⁷Lu-PSMA, which may implicate a flare phenomenon after ¹⁷⁷Lu-PSMA. This has also been described after EBRT, ²²³RaCl₂, chemotherapy, and novel ADTs (32–37).

There were two imaging findings that were remarkable. One patient (patient #1) showed a complete response on PSMA-PET. The treated lymph node in this patient was not detectable on the follow-up PSMA-PET scans (Fig. 4). The other interesting observation was that several tumors (patients #5, #6, #8, and #9) were in regression on the PSMA-PET at the end of the study. This may suggest that ¹⁷⁷Lu-PSMA could have a prolonged genotoxic effect to the tumors with tracer uptake, or that ¹⁷⁷Lu-PSMA could induce an immunogenic cell death.

After two cycles of ¹⁷⁷Lu-PSMA therapy, the median ADT-free survival of all 10 patients was 9.5 months (range 6.5–21 months) with 6 patients still deferring from hormonal treatments. Thus far, the ADT-free survival is less than reported after salvage EBRT or surgery (e.g., STOMP trial: median 21 months; 80% CI, 14–29 months) but can be related to the shorter follow-up time of our study [10.6 months (range, 8.3–21 months); refs. 4, 9, 38]. Moreover, this study included a patient cohort with higher tumor volume, higher Gleason score, and higher PSA velocity compared with those reports. Besides, most patients were already pretreated with salvage EBRT or surgery. Therefore, the observation and comparison with literature has its limitations.

Even though our findings regarding both toxicity and efficacy are performed in a small cohort of selected patients, the results indicate a potential favorable role for ¹⁷⁷Lu-PSMA in patients with hormone-sensitive prostate cancer with low-volume metastatic disease and good PSMA uptake on PET imaging. At least 6 patients had long-lasting PSA responses, especially considering their initial short PSA doubling time. All patients showed only minimal low-grade toxicity after two cycles of ¹⁷⁷Lu-PSMA, with promising tumor to organ radiation dose. Therefore, we assume that higher treatment activity dosages or more treatment cycles are now feasible, with potentially better results. These findings encourage larger prospective studies to provide stronger evidence for the effect of ¹⁷⁷Lu-PSMA in patients with low-volume mHSPC. To investigate this, we recently initiated a randomized controlled multicenter phase II study in the same patient cohort, administering two cycles of 7.4 GBq ¹⁷⁷Lu-PSMA in a 6-week interval (NCT04443062; ref. 39).

¹⁷⁷Lu-PSMA appeared to be a feasible and safe treatment modality in ten patients with low-volume mHSPC. Although the patients were treated with a relatively low dose of ¹⁷⁷Lu-PSMA, the majority of patients showed a promising response to this therapy. This supports the need for following trials to further evaluate the efficacy of ¹⁷⁷Lu-PSMA in low-volume metastatic disease as well as in HSPC.

B.M. Privé reports grants from Dutch Prostate Cancer Foundation and grants from Radboud Oncology Foundation during the conduct of the study. S.M.B. Peters reports grants from Radboud Oncologie Fonds and grants from Prostaatkankerstichting during the conduct of the study. I.M. van Oort reports grants from Radboud Oncologie Fonds and grants from Prostaatkankerstichting during the conduct of the study; I.M. van Oort also reports grants from Astellas, Janssen, Bayer, and MSD/AstraZeneca outside the submitted work. P. Zámecnik reports grants from Radboud Oncologie Fonds and grants from Prostaatkankerstichting during the conduct of the study; P. Zámecnik is a scientific advisor to Saving Patients’ Lives Medical (SPL Medical) B.V., the Netherlands. M.J.M. Uijen reports grants from Radboud Oncologie Fonds and grants from Prostaatkankerstichting during the conduct of the study. A. Eek reports personal fees from Radboud Oncology Fund and personal fees from Dutch Prostate Cancer Foundation during the conduct of the study. W.R. Gerritsen reports grants from Dutch Prostate Cancer Foundation and grants from Radboud Oncology Foundation during the conduct of the study. W.R. Gerritsen also reports personal fees from Merck Sharp & Dohme, ESMO, Bayer, Bristol-Myers Squibb, IMS HealthliQVia, and Janssen-Cilag, as well as personal fees from Sanofi outside the submitted work. N. Mehra reports grants, personal fees, and other from Astellas and Janssen; grants and personal fees from Pfizer, Roche, and Sanofi; and personal fees from BMS and Bayer outside the submitted work. L.G.W. Kerkmeijer reports grants from Prostaatkankerstichting and grants from Radboud Oncology Fund during the conduct of the study. S. Heskamp reports grants from Prostaatkankerstichting and grants from Radboud Oncologie Fonds during the conduct of the study. M. Gotthardt reports grants from Pentixapharm outside the submitted work. J. Nagarajah reports an ongoing IIT using Lu-177 PSMA-617 with in-kind and financial support by Novartis. No disclosures were reported by the other authors.

B.M. Privé: Conceptualization, resources, data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. S.M.B. Peters: Data curation, software, formal analysis, validation, methodology, writing–original draft, project administration, writing–review and editing. C.H.J. Muselaers: Conceptualization, resources, validation, methodology, writing–original draft, project administration, writing–review and editing. I.M. van Oort: Resources, methodology, writing–original draft, writing–review and editing. M.J.R. Janssen: Resources, validation, methodology, writing–original draft, writing–review and editing. J.P.M. Sedelaar: Resources, writing–original draft, writing–review and editing. M.W. Konijnenberg: Software, writing–original draft, writing–review and editing. P. Zámecnik: Resources, methodology, writing–review and editing. M.J.M. Uijen: Resources, writing–original draft, writing–review and editing. M.G.M. Schilham: Resources, writing–original draft, writing–review and editing. A. Eek: Resources, funding acquisition, writing–review and editing. T.W.J. Scheenen: Resources, funding acquisition, methodology, writing–review and editing. J.F. Verzijlbergen: Resources, supervision, funding acquisition, methodology, writing–original draft, writing–review and editing. W.R. Gerritsen: Resources, supervision, methodology, writing–original draft, writing–review and editing. N. Mehra: Resources, methodology, writing–original draft, writing–review and editing. L.G.W. Kerkmeijer: Resources, writing–review and editing. R.J. Smeenk: Resources, writing–review and editing. D.M. Somford: Resources, writing–review and editing. J.-P.A. van Basten: Resources, data curation, software, methodology, writing–review and editing. S. Heskamp: Data curation, software, methodology, writing–review and editing. J.O. Barentsz: Resources, supervision, methodology, writing–original draft, writing–review and editing. M. Gotthardt: Conceptualization, resources, supervision, funding acquisition, methodology, writing–original draft, writing–review and editing. J.A. Witjes: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, visualization, methodology, writing–original draft, writing–review and editing. J. Nagarajah: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, visualization, methodology, writing–original draft, writing–review and editing.

We thank all the investigators of the study, the patients, and their families. This work was supported by Radboud Oncology Foundation and the Dutch Prostate Cancer Foundation (Prostaatkankerstichting).

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