Nordquist, Luke T.

TPS5125 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes. The double PSMA binding moiety of SAR-bisPSMA in 64 Cu-SAR-bisPSMA (imaging) and 67 Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64 Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68 Ga-PSMA-11. Pre-clinical efficacy data of 67 Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition and increased survival in a PC xenograft study. These results led to the development of the SECuRE trial, which aims to assess the safety and anti-tumor efficacy of 67 Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a Phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64 Cu-SAR-bisPSMA and 67 Cu-SAR-bisPSMA in patients with mCRPC. The target population is patients who have progressed despite having at least one androgen receptor pathway inhibitor and demonstrate positivity on 64 Cu-SAR-bisPSMA PET. The study comprises 3 phases: Dosimetry (N=6), Dose Escalation (N~24) and Cohort Expansion (N=24). The 67 Cu-SAR-bisPSMA dose levels investigated in the Dose Escalation Phase are: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and 24 GBq across two doses (cohort 4, two doses at the maximum tolerated dose or maximum feasible dose [MTD/MFD] established in cohorts 1-3; two additional doses may be offered in case of radiological non-progression). In the Cohort Expansion phase, participants will receive 2 doses of 67 Cu-SAR-bisPSMA at the recommended dose determined in the Dose Escalation Phase (those with radiological non-progression may be offered up to 2 additional doses). A recent protocol amendment increased the number of participants from 14 to 24 in the Cohort Expansion phase, in which 8 will receive combination therapy of 67 Cu-SAR-bisPSMA with enzalutamide. The primary and key secondary objectives include assessment of 64 Cu- and 67 Cu-SAR-bisPSMA’s safety and dosimetry and determining the anti-tumor efficacy of 67 Cu-SAR-bisPSMA. Response to 67 Cu-SAR-bisPSMA will be assessed biochemically (≥50% decline in prostate-specific antigen) and radiographically (by RECIST V1.1 and PCWG3). Clinical trial information: NCT04868604 .

TPS294 Background: Approval of [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, previously treated with androgen receptor pathway inhibitors and taxane-based chemotherapy, was based on the results of the Phase 3 VISION study (NCT03511664). It is important to further characterize long-term safety outcomes in 177 Lu-PSMA-617–treated patients, with particular regard to potential treatment-related risks. To this end, the long-term follow-up (LTFU) safety study (NCT05803941) has been established. Findings from the LTFU study will be crucial for assessing delayed toxicities for patients with PSMA-positive metastatic prostate cancer treated with 177 Lu-PSMA-617 globally. Methods: The LTFU study is a prospective, multi-center, non-EU post-authorization safety study. Patients who received ≥1 dose of 177 Lu-PSMA-617 within one of the prospective parent studies (Table 1) are eligible. Patients may enroll in the LTFU study after fulfilling the requirements of their corresponding parent study. The primary endpoint is the number and proportion of selected adverse events (AEs), including myelosuppression, xerostomia, renal failure, xerophthalmia, and second primary malignancies (eg, myelodysplastic syndrome or acute myeloid leukemia), other serious AEs, and changes in laboratory values. The secondary endpoint is the number and proportion of deaths. Following enrollment, patients will undergo assessments at baseline, and then every 6–8 months for up to 10 years after their first dose of 177 Lu-PSMA-617 or until death. At each visit, a review of selected treatment-related AEs (xerostomia, xerophthalmia, myelosuppression), any-cause AEs (renal toxicity, new diagnoses of second primary malignancies), and treatment-related serious AEs will be conducted. Physical and laboratory assessments, as well as details on concomitant medications and interventions, including anti-cancer therapies, will be collected. Patients may receive treatment with any medical intervention. Interim analyses are planned at 2 and 5 years post-study activation. Enrollment is ongoing (n=13). Clinical trial information: NCT05803941 . Parent studies of the long-term follow-up safety study. Trial Indication Phase N (all groups) ClinicalTrials.gov ID VISION (+sub-study) Post-taxane mCRPC 3 831 (+30) NCT03511664 PSMAfore Pre-taxane mCRPC 3 469 NCT04689828 PSMAddition mHSPC 3 1144 NCT04720157 177 Lu-PSMA-617 in patients with moderately or severely impaired, or normal renal function Post-taxane mCRPC 2 20 a NCT06004661 a Planned. mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer.

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

AbstractBackground[177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL).MethodsPost hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong).ResultsIn the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms.ConclusionsIn this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.

TPS5116 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA (NCT04868604). mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST V1.1 and PCWG3. At the time of submission of this abstract, no dose limiting toxicities have been observed to date in the first 3 cohorts. In the United States, 4 sites are active with additional sites in planning. Additional sites in the US and Australia are currently in start-up. Clinical trial information: NCT04868604 .

5010 Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]

5003 Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival vs change of androgen receptor pathway inhibitor (ARPI) in taxane-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). We now present health-related quality of life (HRQoL) and pain outcomes at second interim analysis. Methods: Eligible patients had mCRPC, were candidates for change of ARPI after progression on one prior ARPI, and had ≥1 PSMA-positive and no exclusionary PSMA-negative metastatic lesions by [68Ga]Ga-PSMA-11 PET/CT. Ineligible patients were candidates for PARP inhibition or had received prior systemic radiotherapy, immunotherapy or chemotherapy. Patients were randomized 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq/6 weeks; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients with confirmed radiographic progression on ARPI change could cross over to 177Lu-PSMA-617. Secondary endpoints included time to worsening (TTW) in self-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as a composite of score worsening (prespecified thresholds), clinical progression (including new anti-cancer treatment) or death. Post hoc analyses of TTW in FACT-P and BPI-SF excluded clinical progression and death. The study was not powered for these endpoints and type I error was not controlled. Results: We randomized 468 patients (234/arm) with a median age of 72 years (range, 43–94). Median duration of exposure was 8.4 months for 177Lu-PSMA-617 and 6.5 months for ARPI change. 177Lu-PSMA-617 delayed TTW in FACT-P, EQ-5D-5L and BPI-SF scales and subscales vs ARPI change (Table). Results were similar in non-composite analyses. Incidence of grade ≥3 adverse events (AEs), serious AEs and AEs leading to discontinuation for 177Lu-PSMA-617 and ARPI change were 34% vs 44%, 20% vs 28% and 5.7% vs 5.2%, respectively. Conclusions: 177Lu-PSMA-617 delayed TTW in self-reported pain and HRQoL vs change of ARPI in taxane-naïve patients with PSMA-positive mCRPC. Clinical trial information: NCT04689828 . [Table: see text]

TPS246 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes, warranting the development of new effective therapies in this setting. Prostate-specific membrane antigen (PSMA) is expressed in benign and malignant prostate tissues and luminal surface of salivary/lacrimal glands, small intestine and renal tubules. The double PSMA binding moiety of SAR-bisPSMA in 64Cu-SAR-bisPSMA (imaging) and 67Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68Ga-PSMA-11. Pre-clinical efficacy data of 67Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition compared to the control group as well as a dose-dependent delay in eventual tumor regression in a PC xenograft study. These results led to the development of this clinical study, which aims to assess safety and anti-tumor efficacy of 67Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA. mCRPC patients with progression, prior exposure to at least one androgen receptor pathway inhibitor, and positive 64Cu-SAR-bisPSMA PET may be treated with 67Cu-SAR-bisPSMA. This study is being conducted in 3 phases: a 64Cu-SAR-bisPSMA Dosimetry Phase (n=6), a 67Cu-SAR-bisPSMA Dose Escalation Phase (n=up to 24), and a 67Cu-SAR-bisPSMA Cohort Expansion Phase (n=14). The primary and key secondary objectives include assessment of 64Cu- and 67Cu-SAR-bisPSMA safety and dosimetry, determining the maximum tolerated dose (MTD) or maximum feasible dose (MFD) and anti-tumor efficacy of 67Cu-SAR-bisPSMA. The 67Cu-SAR-bisPSMA dose levels investigated in the escalation phase include: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and up to 24 GBq across two doses (cohort 4, two doses at MTD or MFD). The Dose Expansion Phase of the study will allow the administration of up to 4 doses of 67Cu-SAR-bisPSMA at the MTD/MFD. Response measurements include reduction in PSA levels, radiological progression-free survival, duration of response and overall survival. Radiological response will be assessed by RECIST 1 V1.1 and PCWG3. At the time of submission of this abstract, cohort 3 is open for recruitment and no dose limiting toxicities have been observed to date. Clinical trial information: NCT04868604 .

TPS292 Background: PT-112 is a novel small I-O molecule currently in development for several cancers. Preclinical studies have shown the robust induction of immunogenic cell death by PT-112, leading to an anti-cancer adaptive immune response. Biodistribution experiments in mice showed PT-112’s partial bone affinity. In two prior phase I studies, late-line metastatic castration-resistant prostate cancer patients (mCRPC pts) were treated with evidence of anti-cancer activity, including tumor volume reductions, improvements in PET and bone scans, PSA and alkaline phosphatase (ALP) reductions, and anecdotal cases of improvement in disease-related pain. This, taken together with the immunogenic and osteotropic properties observed in preclinical work, provided a strong rationale to further explore PT-112 in mCRPC, an immunologically “cold” disease with a high prevalence of bone metastases. Moreover, in an analysis of >6,000 mCRPC pts, circulating tumor cell (CTC) declines (CTC0 and CTC conversions) were correlated with improvements in survival to a greater extent than PSA declines (PSA50) (Heller et al., JCO, 36:6 2017), prompting incorporation of CTC changes as a secondary endpoint. Methods: The primary objective of the study is to define the dose regimen of PT-112 for pivotal study. Pts are randomized to one of three arms, receiving IV PT-112 on 28-day cycles via one hour infusions on (1) Days 1 and 15 at 250 mg/m2, (2) Days 1 and 15 at 360 mg/m2, or (3) Days 1 and 15 of cycle 1 at 360 mg/m2 followed by 250 mg/m2 on Day 15 of subsequent cycles. Key eligibility criteria include radiographically progressive disease at study entry; ≥3 life-prolonging therapies for metastatic disease including 1-2 taxanes, ≥1 new generation anti-androgen therapies, and other drugs FDA approved on the basis of survival; and allowing bone-only metastatic disease. Efficacy assessments comprise disease control rate at 4 months (DCR4) using RECIST and PCWG3 criteria, objective response rate, CTC0 and CTC conversion, PSA50 and ALP reductions. Additionally, T cell receptor sequencing is conducted to characterize treatment-induced changes in T cell fraction and clonal expansions, as a means of generating meaningful supportive data on the immune mechanism of PT-112 monotherapy. A Fleming two-stage design will be used to assess each arm, with a 20% DCR4 as the null hypotheses, requiring ≥6 of 25 pts responding in stage one and ≥14 of 45 in total to reject the null. In addition, other efficacy measures, such as CTC responses, as well as exposure/response and exposure/safety analyses will be applied to characterize the risk/benefit ratio and select the optimal dose regimen for PT-112. As of October 11th, 2022, 38 pts have been enrolled out of a planned maximum of 135. Clinical trial information: NCT02266745 .

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]