Tarlatamab Demonstrates Early Safety and Activity in DLL3+ Neuroendocrine Prostate Cancer

Tarlatamab-dlle (Imdelltra; AMG 757) monotherapy elicited responses with acceptable tolerability in patients with neuroendocrine prostate cancer (NEPC), according to data from the phase 1b DeLLpro-300 study (NCT04702737) published in Clinical Cancer Research.1

In terms of safety, treatment-emergent adverse effects (TEAEs) and treatment-related adverse effects (TRAEs) were observed in all patients (n = 40). The most frequently experienced TEAEs included cytokine release syndrome (CRS; 82.5%), decreased appetite (50%), and constipation (45%). The most common TRAEs included CRS (82.5%), dysgeusia (42.5%), decreased appetite (40.0%), pyrexia (37.5%), and fatigue (35%). Grade 3 or higher TRAEs were experienced by 45% of patients and included fatigue (7.5%), hyponatremia (7.5%), CRS (5.0%), diarrhea (5.0%), and lymphopenia (5.0%). TRAEs resulted in dose interruption or reduction for 22.5% of patients and treatment discontinuation for 7.5% of patients. One dose-limiting toxicity was noted in the form of grade 4 immune-mediated encephalopathy. No TRAEs proved to be fatal.

In efficacy-evaluable patients (n = 38), tarlatamab elicited an objective response rate (ORR) of 10.5% (95% CI, 2.9%-24.8%) by RECIST 1.1 criteria; this included 4 patients who achieved a partial response (PR) to treatment. The median duration of response (DOR) was 7.3 months (95% CI, 3.7-not estimable).

Additionally, in those with only DLL3-positive tumors (n = 18), the agent induced an ORR of 22.2% (95% CI, 6.4%-47.6%). The median radiographic progression-free survival (rPFS) in those with DLL3-positive tumors was 3.5 months (95% CI, 1.9-7.4) vs 1.7 months (95% CI, 1.6-2.6) in those with DLL3-negative or unknown tumors; the Kaplan Meier–estimated 6-month rPFS rate in those with DLL3 positivity was 27.7% (95% CI, 8.7%-50.9%). The median overall survival (OS) in those with DLL3-positive vs DLL3-negative or unknown tumors was 9.8 months (95% CI, 4.9-15.2) and 5.5 months (95% CI, 3.0-13.2), respectively.

“The study provided preliminary evidence for tarlatamab activity in DLL3-positive NEPC,” Rahul Aggarwal, MD, of University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues, wrote in the paper. “The study supports further investigation of tarlatamab in DLL3-positive NEPC and highlights the need for optimization of patient identification and selection in this high-risk and heterogeneous patient group.”

What Is the Design of the DeLLpro-300 Study Examining Tarlatamab in NEPC?

The open-label, phase 1b trial enrolled male patients with de novo or treatment-emergent NEPC who were 18 years of age or older and met 1 or more of the following criteria: morphologic evidence of small cell NEPC, positive staining for chromogranin and/or synaptophysin per immunohistochemistry (IHC) in more than 50% of the tumor sample, and/or 2 or more genetic alterations in tumor protein p53, RB1, and/or PTEN observed via IHC or genomic analysis.

To participate, patients must have experienced progressive disease or recurrence following at least 1 line of systemic therapy, which could have been a platinum-based regimen or an androgen-signaling inhibitor. They also needed to have an ECOG performance status no higher than 2.

Patients received tarlatamab at 1 mg on day 1 of cycle 1; this was followed by 100 mg on days 8 and 15 of cycle 1, and then every 2 weeks. Notably, those who experienced radiographic progression by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines were allowed to receive tarlatamab. Before all doses of the agent in cycle 1, patients also received 8 mg of dexamethasone; 1L of normal saline was administered after all tarlatamab doses in the first cycle.

The primary end points of the study were TEAEs and TRAEs, and secondary end points included ORR, DOR, and disease control rate by RECIST v1.1 criteria. Other end points of interest include rPFS by PCWG3 guidelines, OS, and pharmacokinetic profile.

What Should Be Known About the Patient Population Enrolled to DeLLpro-300?

The median patient age was 64.5 years (range, 43-83) and most had an ECOG performance status of 0 or 1 (95%). The median number of prior lines of systemic therapy received was 3 (range, 1-9) and 78% of patients had previously received platinum-based therapy. The median duration from last dose of platinum-based treatment until tarlatamab initiation was 2.9 months (range, 0.9-20.8) and 54.8% of patients experienced disease progression on or within 6 months of their last dose of platinum-based therapy. The majority of patients received previous androgen-based therapy (83%). Patients had visceral (87.5%), liver (65.0%), and bone (55.0%) metastases.

A total of 32 patients had tumor samples deemed evaluable for DLL3 expression. Eighteen of 32 patients had positive DLL3 expression, which was defined as 1% or higher DLL3 tumor positivity per IHC. DLL3 positivity was found in 73% of tumors with small cell morphology (n = 11/15) and 50% of tumors with adenocarcinoma positive for chromogranin and/or synaptophysin (n = 7/14).

The data cutoff date for the final analysis was July 22, 2024, and the median time on study was 6.9 months (range, 1-37). The median duration of treatment was 1.4 months (range, 0.03-35.9).

What Else Was Learned About the Safety Profile of Tarlatamab in NEPC?

All CRS experienced with tarlatamab was observed in the first cycle of treatment and most cases were grade 1 (62.5%) or 2 (15%) in severity. Grade 3 CRS was reported in 5% of cases and patients required high-flow oxygen therapy; no grade 4 or higher cases occurred. The median time between tarlatamab dose and CRS onset was 8.1 hours and the median event duration was 3 days. Five percent of patients who experienced CRS required dose interruption or reduction. All events reportedly resolved.

Additionally, 12.5% of patients who received tarlatamab experienced immune effector cell–associated neurotoxicity syndrome (ICANS); 1 event was grade 4 and resulted in treatment discontinuation and no grade 3 events occurred. All of these events were observed in the first cycle of treatment and the median time from tarlatamab dose to onset of first event was 5.5 days.

What Was the Efficacy of Tarlatamab According to DLL3 Status?

In those with DLL3-negative tumors (n = 13), 15.4% experienced stable disease (SD); 46.2% of patients had progressive disease and 38.5% had no post-baseline scan. In those with DLL3 status unknown tumors (n = 7), 85.7% of patients experienced disease progression and 14.3% did not have a post-baseline scan. The activity was limited to those with DLL3-positive tumors (n = 18), with a PR rate of 22.2% and a SD rate of 33.3%; 27.8% of patients experienced disease progression and 16.7% did not have a post-baseline scan.

What Is the Key Take-Home Message Regarding Tarlatamab in NEPC?

“Our findings provide preliminary support for the activity of tarlatamab in DLL3-positive NEPC and highlight the need for improved approaches to define metastatic castration-resistant prostate cancer subsets (including NEPC) and identify therapeutic targets in this high-risk population,” the study authors concluded.

Data from the study were previously presented at the 2024 ASCO Annual Meeting.2 In May 2024, the FDA granted accelerated approval to tarlatamab for use in extensive-stage small cell lung cancer with disease progression on or following platinum-based chemotherapy.3 In an exclusive interview with OncLive®, Taofeek Owonikoko, MD, PhD, of University of Maryland Marlene and Stewart Greenebaum Cancer Center and University of Maryland Medical Center, further discussed the significance of the decision, in which he said that the potential benefits and manageable safety profile of the agent make it a clinically viable option for patients who progressed following first-line chemotherapy.4

References

1. Aggarwal R, Rottey S, Bernard-Tessier A, et al. Safety and efficacy of tarlatamab in patients with neuroendocrine prostate cancer: Results from the phase 1b DELLpro-300 study. Clin Cancer Res. 2025;31(18):3854-3863. doi:10.1158/1078-0432.CCR-25-1211
2. Aggarwal RR, Rottey S, Bernard-Tessier A, et al. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2024;42(16):5012.doi:10.1200/JCO.2024.42.16_suppl.5012
3. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed October 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
4. Owonikoko T. Dr Owonikoko on the impact of the FDA approval of tarlatamab in ES-SCLC. OncLive.com. June 28, 2024. Accessed October 13, 2025. https://www.onclive.com/view/dr-owonikoko-on-the-impact-of-the-fda-approval-of-tarlatamab-in-es-sclc