October 21, 2023
Immune Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer
By Catlin Nalley
Phase I findings demonstrated that treatment with xaluritamig was tolerable—with low-grade cytokine release syndrome—among heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC). This data, which was recently presented by William K. Kelly, DO, Chair of the Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, during the European Society for Medical Oncology (ESMO) Congress 2023, held October 20-24 in Madrid, Spain, also showed encouraging preliminary efficacy in this patient population (Abstract 1765O).
“Prostate cancer remains a leading cause of cancer deaths worldwide, and patients with metastatic castration-resistant prostate cancer have a poor prognosis,” he noted during his ESMO presentation. “STEAP1 is a cell surface antigen that is highly expressed in prostate cancer and expression of STEAP1 is associated with higher Gleason scores and worse prognosis in prostate cancer.”
Xaluritamig is a 2+1 T-cell engager designed to facilitate T cell-mediated lysis of STEAP1-expressing cells, Kelly explained. “In preclinical models, xaluritamig showed broad anti-cancer effects in prostate cancer cell lines and xenograft models, supporting the initiation of clinical trials.”
Methods & Findings
Kelly and colleagues initiated a global, first-in-human, open-label study of xaluritamig in patients with advanced prostate cancer. The primary objectives of this study include the assessment of safety and tolerability, as well as maximum tolerated dose. Secondary objectives included PK and preliminary anti-tumor activity.
Eligible patients had metastatic castration-resistant prostate cancer refractory to prior novel hormonal therapy and 1-2 taxane regimens, ECOG performance status 0-1, and adequate organ function. Patients with histology other than adenocarcinoma and active autoimmune disease were excluded.
“Patients in this study were heavily pretreated with a median of four prior lines of therapy. Eight-five percent had prior taxane-based therapy,” said Kelly, while also noting visceral metastases in 53 percent of patients, 37 percent of which have liver disease. “This is a really high-risk population.”
Xaluritamig was administered as an IV weekly (QW) or Q2W with various dose levels/schedules, according to Kelly and colleagues. Below, initial results of the study’s dose exploration portion are discussed; the dose expansion portion is ongoing.
Ninety-seven patients received at least one intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks, reported Kelly. “The maximum tolerated dose was identified as 1.5 mg IV weekly via a three-step dose, starting with 0.1 mg on Day 1, escalating to 0.3 mg on Day 8, 1.0 mg on Day 15, and 1.5 milligrams Day 22 onward.”
When discussing the safety profile during dose exploration, Kelly said it was generally manageable. “Ninety-seven percent of patients experience treatment-related adverse events and 19 percent of patients had an adverse event that led to discontinuation,” he reported, while noting that there were few Grade 3 adverse events and no related Grade 4 or 5 events.
Adverse events were generally consistent with the mechanisms of action, such as cytokine release syndrome, and patient populations, such as anemia and fatigue, according to Kelly. Treatment-related adverse events of musculoskeletal and connective tissue disorders were reported, of which 14 percent were serious. Cytokine release syndrome occurred primarily in Cycle 1, was low grade, and manageable.
Confirmed PSA responses were observed across all cohorts, according to Kelly. Of the 87 patients evaluable for PSA, PSA50 and PSA90 responses occurred in 43 (49%) and 24 (28%) patients, respectively. PSA responses were more frequent at higher dose levels (7b-13) versus lower dose levels (1-7a).
Of 43 patients in the low-dose cohort, 17 (40%) had a PSA50 response and eight (19%) had a PSA90 response. Comparatively, of the patients in the high dose cohort (n=44), PSA50 and PSA90 responses occurred in 26 (59%) and 16 (36%) patients, respectively.
“If we look at measurable disease, 67 out of 97 patients in this trial, approximately two-thirds of patients, had evaluable disease,” said Kelly. “This is higher than historical benchmarks, depicting the high-risk population that we are treating.”
RESIST responses included 16 (24%) partial responses, 32 (48%) stable disease, and 13 (19%) progressive disease. “The partial response rate was 41 percent in high dose and 3 percent in low dose,” Kelly noted. Nineteen patients from high-dose cohorts remained on treatment at data cutoff. Of those, 13 patients from high-dose cohorts remained on treatment for more than 6 months.
“While preliminary data on duration of response are immature, the median duration of response is currently 9.2 months among the 60 patients with confirmed partial responses, with 10 patients still in response,” Kelly said. “With longer follow-up, additional data on durability and progression-free survival will be important to understand the overall clinical benefit of xaluritamig.”
This research, which was simultaneously published in the journal Cancer Discovery (2023; https://doi.org/10.1158/2159-8290.CD-23-0964), is encouraging, according to Kelly. “These results support ongoing dose-expansion optimization of the drug to advance the development of xaluritamig as a potential treatment option in patients with metastatic castration-resistant prostate cancer, both as a monotherapy and a combination treatment,” he concluded.
Catlin Nalley is a contributing writer.