Progressive Metastatic Castration-resistant Prostate Cancer Research Articles

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial

Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA.

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .

Intra-individual dose escalation of abiraterone (ABI) according to its plasma exposure in patients (pts) with progressive metastatic castration-resistant prostate cancer (mRCPC): Results of the OPTIMABI trial.

159 Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) < 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI study, a multicenter non-randomized study (NCT 03458247), aimed to investigate whether a dose escalation of ABI improve PFS in underexposed progressive mCRPC pts. Methods: In step 1, pts with docetaxel-naive progressive mCRPC received ABI at the standard dose of 1000 mg/d + Prednisone 10 mg/d. Mean ABI Cmin was calculated from three monthly dosages. Pts experiencing progression within the first 6 ms and for whom mean ABI Cmin was < 8.5 ng/mL were included in step 2 and received 1000 mg twice daily (2000 mg/d) of ABI. ABI Cmin was assessed every month. The primary endpoint was the non-progression rate at 12 weeks in step 2. Identification of risk factors of 6 ms-PFS was done using Cox regression analysis. Results: From 06/2018 to 09/2021, 81 of 93 pts (median age: 72 yrs) included in step 1 were evaluable for statistical analysis. The median ABI Cmin was 10.0 (IQR: 4.5-15. 0) ng/mL over the first three ms. Inter-individual variability was 59%. The 6 ms-PFS was 68% (IC 95%: 56% - 80%) with no statistical difference between pts with mean ABI Cmin ≥ or < 8.5 ng/mL (log-rank test, p= 0.24). In multivariate analysis, liver metastasis (Hazard ratio, HR = 5.95, CI95% = 1.22–28.92; p=0.027) and creatinine clearance < 60 mL/min (HR = 3.51, CI95% = 1.12–10.99; p=0.031) were independently associated with 6 ms-PFS. Among 21 pts (25.9%), with mean ABI Cmin < 8.5 ng/mL, 8 pts (38.1%) experienced tumor progression within the first 6 ms; four of them could be included in step 2. None of them fulfilled the primary endpoint despite a significant increase in plasma ABI Cmin (p <0.036 by paired t-test). Conclusions: Despite high inter-individual variability of mean ABI Cmin, the OPTIMABI study does not support the strategy of intra-individual dose escalation according to plasma concentration of ABI in mCRPC. Underexposure to ABI (ABI Cmin < 8.5 ng/mL) was not statistically associated with shorter PFS. Clinical trial information: NCT03458247 .

A Single-Arm, Low-Dose, Prospective Study of 177Lu-EB-PSMA Radioligand Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

We aimed to investigate the safety and therapeutic efficacy of radioligand therapy (RLT) of 177Lu-EB-prostate-specific membrane antigen (PSMA) in patients with metastatic castration-resistant prostate cancer. Methods: Thirty men with progressive metastatic castration-resistant prostate cancer previously treated with taxane-based chemotherapy and second-generation androgen deprivation therapy were enrolled. All patients received up to 3 cycles of approximately 2.0 GBq (55 mCi) of 177Lu-EB-PSMA per cycle at 8-wk intervals. The primary endpoint was therapeutic safety, including changes in hematologic status, liver function, and renal function. An additional primary endpoint was therapeutic efficacy, including prostate-specific antigen (PSA) response and molecular imaging response. The secondary endpoints were PSA progression-free survival (PFS) and overall survival (OS). Another endpoint was patient-reported health-related quality of life. Results: From January 2019 to December 2021, 30, 22, and 11 patients received 1, 2, or 3 cycles of 177Lu-EB-PSMA RLT, respectively. During the entire follow-up period, 33.3% of patients experienced grade 3 hematologic adverse events. Seventeen (56.7%) patients achieved a PSA reduction of at least 50%. The median PSA PFS was 4.6 mo (95% CI, 2.7-6.5 mo), and the median OS was 12.6 mo (95% CI, 8.1-17.1 mo). A higher whole-body PSMA SUVmean correlated with a better PSA response, higher baseline alkaline phosphatase and larger total PSMA-positive tumor volume were associated with worse PSA PFS, and the existence of visceral metastases and higher PSA value at baseline were significant prognosticators of worse OS. Health-related quality-of-life outcomes improved significantly after 177Lu-EB-PSMA RLT. Conclusion: RLT based on approximately 2.0 GBq of 177Lu-EB-PSMA for up to 3 cycles may achieve a PSA response and hematologic toxicity comparable to those from 7.4-GBq doses of 177Lu-PSMA-617 for up to 4-6 cycles. Further studies with more cycles of 177Lu-EB-PSMA RLT are needed to evaluate the potential benefits in terms of PFS and OS.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial

BackgroundAntagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC.MethodsThis phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12.ResultsA total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0–74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2–95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7–47.7) of 61 patients.ConclusionSHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study.Trial registrationClinicaltrials.gov NCT02691975; registered February 25, 2016.

Improvements in symptoms related to bone metastasis in recipients of Lutetium-177 PSMA-617 for prostate cancer.

96 Background: Prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) targeted to prostate-specific membrane antigen (PSMA) is a new targeted treatment for progressive metastatic castration-resistant prostate cancer (mCRPC). PSMA-RLT conjugates a radionuclide to a small molecule ligand with affinity for PSMA. Recent trials, such as TheraP and VISION, established improvements in progression free survival, overall survival, and patient-reported outcomes (PROs) for PSMA-RLT. Less is known about the impact of PSMA-RLT on symptoms related to bone metastasis (BM), commonly causing significant morbidity in men with mCRPC. The optimal tools for PRO collection with PSMA-RLT are also uncertain. We previously reported improvements in Brief Pain Inventory and now report EORTC QLQ-BM22 data to describe change in symptoms related to bone metastasis among men receiving PSMA-RLT for mCRPC. Methods: From 2015 to 2017, 50 patients received up to 4 cycles of 177Lu-PSMA-617 every 6 weeks (trial registration: ACTRN12615000912583). Patients completed a validated assessment of bone metastasis-related pain (EORTC QLQ-BM22) prior to each cycle and 6 or 12 weeks after the last cycle of 177Lu-PSMA. Change in pain over the course of the study was examined using linear mixed effects models. We also examined whether unadjusted changes in PROs exceeded published cutoffs for minimal clinically important difference scores. Results: Patients reported reduced bone metastasis-related pain at various sites over time ( p =.01). Of 44 patients completing this scale before cycle 2, 22 (50%) reported clinically significant improvement in pain at various sites. At follow-up, of the 37 patients alive, 25 provided evaluable data on bone metastasis-related pain. Of these, 10 (40%) reported clinically significant improvement in pain at various sites. Patients also reported less functional interference from pain over time ( p <.01) and lower consistency, intermittency, and difficulty alleviating pain with medication over time ( p =.01). Before cycle 2 and at follow-up, 26% and 38% of respondents reported clinically significant reduction in functional interference from pain. Before cycle 2 and at follow-up, 33% and 42% of respondents reported clinically significant improvement in consistency, intermittency, and difficulty alleviating pain with medication. Conclusions: 177Lu-PSMA RLT resulted in improvements in bone metastasis-related symptoms, supporting prior findings using other PRO measures. At follow-up, 38-42% of patients completing PRO assessment reported clinically meaningful improvements in bone metastasis-related pain, a significant contributor to quality of life. Clinical trial information: ACTRN12615000912583.

Mobile Audio Recording Technology to Promote Informed Decision Making in Advanced Prostate Cancer.

Men with metastatic castration-resistant prostate cancer increasingly encounter complex treatment decisions. Consultation audio recordings and summaries promote patient informed decision making but are underutilized. Mobile recording software applications may increase access. Little is known regarding the feasibility of implementation in clinical encounters. We conducted a mixed-methods pilot study in men with progressive metastatic castration-resistant prostate cancer. We instructed patients to use a mobile software application to record an oncology visit. Patients could share the recording with our patient scribing program to receive a written summary. We assessed feasibility and acceptability with postvisit surveys. We measured patient-reported helpfulness of the intervention in decision making and change in Decisional Conflict Scale-informed subscale. We conducted semistructured interviews to explore implementation and analyzed transcripts using thematic analysis. Across 20 patients, 18 (90%) recorded their visits. Thirteen of 18 (72%) listened to the recording, and 14 of 18 (78%) received a summary. Eighteen of 20 (90%) visits were telehealth. Fourteen patients (70% of all 20; 78% of 18 question respondents) found the application easy to use. Nine patients (50% of 18 recording patients; 90% of 10 question respondents) reported that the recording helped treatment decision making. Decisional conflict decreased from baseline to 1-week postvisit (47.4-28.5, P < .001). Interviews revealed benefits, facilitators, contextual factors, and technology and patient-related barriers to recordings and summaries. In this single-institution academic setting, a mobile application for patients to record consultations was a feasible, acceptable, and potentially valued intervention that improved decision making in the telehealth setting. Studies in larger, diverse populations are needed.

629P Patient-reported outcomes in prostate cancer patients receiving PSMA-targeted radionuclide therapy

Prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) is a promising investigational therapy for patients with progressive metastatic castration-resistant prostate cancer. PSMA TRT conjugates a radionuclide emitting alpha radiation (e.g., Actinium-225) or beta radiation (e.g., Lutetium-177) to a small molecule ligand (e.g., PSMA-617) or a monoclonal antibody (e.g., J591) that has affinity for PSMA. Treatment is generally well-tolerated, but adverse events have been reported.

Salvage Radioligand Therapy with Repeated Cycles of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer with Diffuse Bone Marrow Involvement

Simple SummaryMetastatic castration-resistant prostate cancer (mCRPC) with extensive spread to the bone marrow is an incurable stage of disease associated with a poor prognosis and a high risk of impaired blood cell formation. Therapeutic options prolonging survival are limited and may result in significant bone marrow toxicity. The concept of radioligand therapy (RLT) in mCRPC is marked by the targeted delivery of radionuclides, such as beta particle emitting 177Lutetium (177Lu) to the prostate-specific membrane antigen (PSMA), a transmembrane protein frequently present on prostate cancer cells. RLT has yielded promising anti-tumoral activity and excellent tolerability in patients with mCRPC as shown by multiple retrospective series and a growing number of prospective trials. The presented study aims to investigate the role of RLT in mCRPC patients with metastases diffusely involving the bone marrow. Special emphasis is laid on identifying early indicators for a favorable treatment response and potential risk factors for adverse outcomes. The impact of RLT-specific variables, including administered treatment activity, cumulative activity and whole-body absorbed dose is assessed individually.Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with 177Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq 177Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0–9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2–12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18–8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000–1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with 177Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

The impact of the extent of the bone involvement on overall survival and toxicity in mCRPC patients receiving [177Lu]Lu-PSMA-617: a WARMTH multicentre study.

Prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement. The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with [177Lu]Lu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6-20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18months (less than 6 lesions), 13months (6-20 lesions), 11months (more than 20 lesions) and 8months (diffuse involvement), respectively (p < 0.0001). Patients with prior Ra-223-therapy showed longer OS in all subgroups, especially in the subgroups with 6-20 lesions (OS: 16 vs. 12months; p = 0.038) as well as diffuse involvement (OS: 11 vs. 7months; p = 0.034). Significant negative prognosticators of OS were the existence of liver metastases in all subgroups and prior chemotherapy in patients with <6 bone lesions. Anaemia and thrombocytopenia correlated positively with the extent of bone metastases: p < 0.0001 and 0.005, respectively. No patient showed a high grade leukopenia. The extent of bone involvement correlated negatively with the OS after RLT; however, it showed no relevant correlation with the PSA response rate. Prior therapy with Ra-223 may have a positive impact on OS. Haematotoxicity was higher in patients with more than 20 bone lesions; nevertheless, the majority of these patients did not show a relevant haematotoxicity.

Radium-223 (Ra-223) versus novel antihormone therapy (NAH) for progressive metastatic castration-resistant prostate cancer (mCRPC) after 1 line of NAH: RADIANT, an international phase 4, randomized, open-label study.

TPS5093 Background: Men with mCRPC often receive sequential NAH (abiraterone and enzalutamide) despite reported cross-resistance, indicating a need for further life-prolonging options for progressive disease after prior NAH. Ra-223 is a targeted alpha therapy approved for mCRPC with symptomatic bone metastases based on the phase 3 ALSYMPCA study, in which it demonstrated significantly increased overall survival (OS), reduced symptomatic skeletal event (SSE) risk, improved quality of life, and reduced treatment-emergent adverse event rates vs placebo. As life-prolonging therapy is increasingly used in hormone-sensitive settings, this study has been designed to assess Ra-223 outcomes in patients with mCRPC that progressed after prior treatment with NAH and docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC. Methods: This study is conducted in accordance with the Declaration of Helsinki, international ethical and good clinical practice guidelines, and local laws and regulations, with institutional review board/ethics committee approval at each site and written informed consent from patients before participation. This trial is registered with EudraCT: 2019-000476-42. Participants must be ≥18 years old, with an Eastern Cooperative Oncology Group performance status of 0/1; they must have mCRPC that progressed on/after ≥3 months of NAH for mHSPC or mCRPC and ≥2 cycles of docetaxel unless they refused or were ineligible, with ≥2 bone metastases on bone scan, no visceral metastases, and a worst pain score ≥1 on the Brief Pain Inventory-Short Form. Patients are randomized 1:1 to Ra-223 or NAH: Ra-223 55 kBq/kg intravenously every 4 weeks for 6 cycles or until disease progression, death, or withdrawal of consent if earlier; or abiraterone 1000 mg + prednisone 10 mg daily (if prior enzalutamide) or enzalutamide 160 mg daily (if prior abiraterone) until disease progression, death, or withdrawal of consent. NAH dosing may be modified to manage adverse events. Patients must use luteinizing hormone-releasing hormone analogs, if not surgically castrated, and bone health agents (bisphosphonates or denosumab) throughout the study. The primary endpoint is OS. Secondary endpoints are time to first SSE, radiologic progression-free survival, time to pain progression, adverse events, fracture incidence, and time to deterioration in quality of life (FACT-P total score). Using a test with a two-sided alpha of 0.05, 90% power, and randomization ratio of 1:1, approximately 508 events are required to detect a 33% increase in OS with Ra-223 vs NAH, assuming a median OS of 10 months with NAH. The expected study duration is 55 months, with a target of 696 patients to be randomized. The first patient was enrolled on November 9, 2020; 5 patients have been randomized and 2 have started treatment to date. Clinical trial information: 2019-000476-42.

286P Efficacy, safety and pharmacokinetics (PK) of enzalutamide (ENZ) vs placebo (PL) in chemotherapy-naive patients (pts) with progressive metastatic castration-resistantprostate cancer(mCRPC):AnAsianmultinationalstudy

286P Efficacy, safety and pharmacokinetics (PK) of enzalutamide (ENZ) vs placebo (PL) in chemotherapy-naive patients (pts) with progressive metastatic castration-resistantprostate cancer(mCRPC):AnAsianmultinationalstudy

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade &gt; 3 heme toxicity or grade &gt; 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had &gt; 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

Predictive factors of tumor sink effect: Insights from 177Lu-Prostate-specific membrane antigen therapy

Tumor sink effect (TSE) has been defined as; decreased uptake in healthy tissue with increased tumor sequestration of the radiopharmaceuticals. It enables us to give high tumoral radiation doses while resulting in lower absorbed radiation to critical organs. However, the factors which influence this effect are yet to be defined. In this study, we have investigated the predictive factors of the tumor sink effect in a group of patients who received 177Lu-Prostate-specific membrane antigen (PSMA) therapy due to progressive metastatic castration-resistant prostate cancer (mCRPC). We have retrospectively analyzed the pre-therapy 68Ga-PSMA positron-emission tomography (PET)-computed tomography (CT) and post-therapy planar whole-body scans of 65 patients who received at least two cycles of 7.4GBq of 177Lu-PSMA therapy. All patients with mCRPC were referred to our department after multiple treatment lines. Age, previous therapies, International Society of Urological Pathology (ISUP) score, and pre-therapy serum tumor marker levels were recorded. Post 177Lu-PSMA therapy images were analyzed for TSE. 68Ga-PSMA PET-CT images were used for the calculation of SUVmax in malignant and healthy tissues as well as metabolic tumor volume (MTV) and total lesion PSMA index (TLPI). Based on the post-therapy scans, TSE was seen in 17/65 (26.2%) patients. In univariate analysis, patients with TSE had higher pre-therapy PSA, PSA velocity, and ALP (p < 0.0001). In relation to PET parameters, patients with TSE had higher 68Ga-PSMA MTV, 68Ga-PSMA TLPI and lower pretherapy renal SUVmax (p < 0.0001)), pretherapy liver SUVmax (p:0.012), pretherapy parotid gland SUVmax (p:0.032), and pretherapy parotid gland SUVmean (p:0.038). In the multivariant analysis, 68Ga-PSMA TLPI, pre-therapy PSA, and PSA velocity were found to be statistically significant. When analyzed according to Youden index, pretherapy PSA level of 133ng/ml (sensitivity 0.765 and 0.875), PSA velocity of 246ng/ml/year (sensitivity 0.765 and 0.833), and 68Ga-PSMA TLPI of 2969g (sensitivity 0.765 and 0.875) was found to be the best cut-off points to predict TSE. The tumor sink effect was seen in 26.2% of patients. 68Ga- PSMA TLPI, pre-therapy PSA, and PSA velocity was found to be the predictors of TSE. Accurate prediction of TSE may lead to increased tumoral doses while sparing healthy organs. Clinical trials that consider this effect as a part of a dose algorithm may further increase therapeutic efficacy.

ADRB2 expression in progressive metastatic castration-resistant prostate cancer.

145 Background: The net oncogenic effect of the G protein-coupled receptor β2 adrenergic receptor ADRB2, which may induce neuroendocrine differentiation via cyclic AMP and protein kinase A and whose expression is epigenetically regulated by EZH2, is controversial. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: This was a retrospective analysis of a cohort of men with mCRPC who were prospectively enrolled in the multi-center SU2C/PCF/AACR West Coast Prostate Cancer Dream Team study, in which biopsies of a metastatic site were obtained at disease progression. Specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and transcriptional cluster based on prior unsupervised hierarchical transcriptome clustering, and correlated with EZH2 expression. ADRB2 expression (lowest quartile) was correlated with OS from time of biopsy by log rank test and a multivariable Cox proportional hazard model. Results: One-hundred and twenty-seven men with progressive mCRPC underwent metastatic biopsies and had sufficient tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P&lt;0.001), and correlated inversely with EZH2 expression (r=-0.28, P&lt;0.01). Men with low ADRB2 expression had a shorter median OS than those with high (9.5 vs 18.9 mo, P=0.02). In multivariable analysis adjusting for small cell histology, performance status, LDH, and visceral metastases, high ADRB2 expression was associated with a trend towards longer OS (HR=0.65, 95% CI 0.41-1.02, P=0.06). Conclusions: Low ADRB2 expression is associated with worse OS in men with progressive mCRPC, and may be a means by which EZH2 confers resistance to antiandrogen therapy. Indirect ADRB2 stimulation with EZH2 inhibitors may improve outcomes. Validation in independent cohorts is necessary.

Patient-reported outcomes (PRO) from a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC).

45 Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% &gt;2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177Lu-J591. 59.1% with &gt;50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe with fractionated (D1 &amp; D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.

KEYNOTE-046 (Part B): Effects of ADXS-PSA in combination with pembrolizumab on survival in metastatic, castration-resistant prostate cancer patients with or without prior exposure to docetaxel.

126 Background: ADXS-PSA, an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), is currently being evaluated in combination with pembrolizumab as a treatment for progressive metastatic castration-resistant prostate cancer (mCRPC) in the phase 1/2 KEYNOTE-046 trial (Part B). Methods: A total of 37 patients received 1x109 CFU + 200 mg pembro IV every 3 wks, for up to 2 yrs or until progression/toxicity. Results: At entry, patients were ~70 yrs with median a Gleason score of 9, and bone predominant disease (70%). MSI-High was negative in 36 pts who were able to be tested. Eighteen (48.6%) patients had received prior docetaxel, 15 pts of whom (83.3%) had also received 1-2 next generation hormonal agents (NGHAs). Nineteen (51.3%) had not received prior docetaxel and 16 of these pts (84.2%) had received 1-2 NGHAs. Overall, 16 out of 37 pts (43%) had a decreased PSA post-BL with 6/37 (16%) pts achieving a confirmed PSA reduction ≥50% from baseline. The median OS (months) for the whole group (37 pts) was 33.6 m (95% CI, range 15.4-33.6 months). The mOS for pts with and without prior exposure to docetaxel was 16 m (5.9 -33.6) and NR at 30 months of follow-up (15.4-NR), respectively. Prolonged survival was observed in pts regardless of prior therapies, microsatellite stable (MSS) status or PSA delta &lt;50% or ≥50%. Conclusions: Results with ADXS-PSA in combination with pembrolizumab in mCRPC, with or without prior docetaxel, show promising clinical activity to be further assessed in randomized studies. Clinical trial information: NCT02325557.

VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

TPS259 Background: The novel therapeutic drug 177Lu-PSMA-617 is a prostate-specific membrane antigen (PSMA) targeting agent that is used to deliver radionuclide therapy for the treatment of patients with mCRPC. Based on preclinical data that demonstrated high PSMA binding affinity and internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development. Preliminary clinical data indicates that 177Lu-PSMA-617 may demonstrate clinical benefit in patients with mCRPC in a setting where patients had no clear standard of care. VISION (NCT03511664) is a phase 3 study designed to assess the efficacy of 177Lu-PSMA-617 in patients with PSMA-positive mCRPC. Methods: Patients were randomized 2:1 to receive best standard of care with or without 177Lu-PSMA-617. Eligibility criteria were: PSMA expressing tumor assessed by PSMA positron emission tomography imaging; prior exposure to a taxane and a novel androgen axis inhibitor (NAAI). The primary objective of this study is to compare the two alternative endpoints of progression-free survival (rPFS) and overall survival (OS). Stratification factors include lactate dehydrogenase, liver metastasis, ECOG PS, and use of an NAAI at time of randomization. On active treatment, median OS is assumed to be 13.7 months with a hazard ratio (HR) of 0.7306, and rPFS is assumed to be 6 months with an HR of 0.67. Enrollment began in June 2018 and the target of 814 patients has been reached. Clinical trial information: NCT03511664.

Pilot Study of Hyperfractionated Dosing of Lutetium-177-Labeled Antiprostate-Specific Membrane Antigen Monoclonal Antibody J591 (177 Lu-J591) for Metastatic Castration-Resistant Prostate Cancer.

Hyperfractionation of lutetium-177 (177 Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177 Lu-J591 or fractionated two-dose 177 Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177 Lu-J591 (also known as TLX591) is planned and will use the two-dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). Phase I and II single-dose studies of lutetium-177 (177 Lu)-J591, a radio-labeled antibody binding prostate-specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177 Lu-J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. Men with progressive metastatic castration-resistant prostate cancer and adequate organ function were enrolled. 177 Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177 Lu-J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75-150 mCi/m2 ). Two (33%) patients had >30% prostate-specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. Hyperfractionation of 177 Lu-J591 is feasible but does not seem to have significant advantages over the two-dose fractionation regimen.