(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on prostate cancer, and a presentation by Dr. Rahul Aggarwal discussing results of a phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer. Tarlatamab, is a bispecific T-cell engager immunotherapy that directs cytotoxic T cells to cancer cells expressing delta-like ligand 3 (DLL3):
DLL3 is aberrantly expressed on high grade neuroendocrine tumors, including small cell lung cancer and neuroendocrine prostate cancer. Tarlatamab has demonstrated encouraging clinical activity and a manageable safety profile in small cell lung cancer. Neuroendocrine prostate cancer is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. It is characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma, in 10–15% of mCRPC patients. At the 2024 ASCO annual meeting, Dr. Aggarwal and colleagues reported the primary analysis data from the DeLLpro-300 phase 1b study, evaluating tarlatamab 100 mg IV every 2 weeks in de novo or treatment emergent neuroendocrine prostate cancer.
This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years) patients with metastatic de novo or treatment-emergent neuroendocrine prostate cancer by histologic, genomic, or immunohistochemistry criteria. The starting dose was the highest safe and tolerable dose in the phase 1 small cell lung cancer trial (NCT03319940). The trial design is highlighted as follows:
Safety was the primary objective, while anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by immunohistochemistry using the Ventana SP347 assay.
As of March 28 2023, 40 patients received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). The median age was 64.5 (range: 43–83) years, median number of prior lines of therapy was 3 (range: 2–4), and median PSA at baseline was 0.2 (range: 0–5000) μg/L:
Treatment-related adverse events occurred in all patients, with no fatal treatment-related adverse events. The most common treatment-related adverse events were cytokine-release syndrome (75.0%), pyrexia (52.5%) and dysgeusia (42.5%):
Cytokine-release syndrome occurred primarily in treatment cycle 1 and events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to treatment-related adverse events was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab small cell lung cancer studies. Retrospective DLL3 immunohistochemistry analysis showed that 18 of 32 (56.3%) biopsy evaluable patients had ≥1% DLL3 tumor positivity (DLL3+). The objective response rate per RECIST v1.1 was 10.5% (95% CI, 2.9, 24.8) and was 22.2% (95% CI, 6.4, 47.6) in DLL3+ patients. Overall, the median duration of treatment was 1.4 months and was 3.6 months in the DLL3+ patients. Median duration of response in all patients was 7.3 months (95% CI 3.7-NE) and one patient remains on treatment with an ongoing response at 25.8+ months:
Overall, the median progression free survival was 2.1 months (95% CI 1.7-3.7). Among DLL3+ patients, median progression free survival was 3.7 months (95% CI 1.9-7.4). For overall survival, the median survival was 7.9 months (95% CI 4.4-13.2) for all patients, and 9.8 months (95% CI 4.9-15.2) for DLL3+ patients:
The following images are of a patient with high DLL3 expression and a partial response to treatment:
Dr. Aggarwal concluded his presentation discussing initial results of a phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer with the following take home messages:
- Findings from this phase 1 study evaluating tarlatamab 100 mg IV every 2 weeks in patients with neuroendocrine prostate cancer demonstrated a manageable safety profile
- Cytokine release syndrome was common, transient, and mostly grade 1
- The safety profile was comparable to that reported with tarlatamab 100 mg treatment in small cell lung cancer
- Broad inclusion criteria for neuroendocrine prostate cancer and lack of requirement for DLL3 expression appeared to limit the anti-tumor activity observed in the overall study population
- However, encouraging anti-tumor activity was seen in the DLL3 positive subset of patients
- Objective response rate in DLL3+ patients was 22.2 % with durable responses observed, including one patient who remains on treatment with ongoing response for 25+ months
- These findings provide preliminary support for tarlatamab’s activity in DLL3+ prostate cancer and highlight the need for novel approaches to diagnose neuroendocrine prostate cancer and identify actionable therapeutic targets in this population with high unmet needs
Presented by: Rahul R. Aggarwal, University of California, San Francisco, San Francisco, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024