Adding cixutumumab to ADT did not significantly increase the undetectable PSA rate in men with newly diagnosed metastatic hormone-sensitive prostate cancer.
Adding cixutumumab to androgen deprivation therapy (ADT) did not significantly increase the undetectable prostate-specific antigen (PSA) rate in men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, according to results of the Southwest Oncology Group (SWOG) S0925 study published in the Journal of Clinical Oncology.
Evan Y. Yu, MD, of the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, and colleagues randomized 210 patients to receive either ADT (bicalutamide and luteinizing hormone–releasing hormone agonist) alone or ADT plus cixutumumab. At 28 weeks, the undetectable PSA rate (≤ 0.2 ng/mL) was 40% (42 of 105 patients) in the cixutumumab arm compared with 32.3% (34 of 105 patients) in the ADT-alone arm (relative risk = 1.24, P = .16).
The median age of patients in the trial was 65, and the median PSA levels in the control and cixutumumab arms were 31 ng/mL and 37 ng/mL, respectively.
Level of circulating tumor cells (CTCs) were evaluated as a secondary endpoint and appeared to have a prognostic value. A lower CTC count prior to treatment was associated with a higher rate of PSA response (P = .036); 39 patients had a CTC count of 0 prior to starting therapy. In total, 50 patients were evaluable for CTCs at baseline.
Cixutumumab is a recombinant human monoclonal immunoglobulin G1 antibody against the insulin-like growth factor 1 receptor (IGF-1R). IGF-1R signaling can stimulate the translocation of the androgen receptor to the nucleus and results in androgen receptor–mediated signaling even when androgens are absent.
In the S0925 trial, IGF-1R biomarkers did not correlate with PSA outcome, and cixutumumab did not appear to change the levels of these biomarkers.
In a hormone-sensitive prostate cancer xenograft model, cixutumumab was synergistic in combination with castration, providing the rationale for the current study.
Prior early-stage studies have shown that cixutumumab can result in radiographic stabilization among patients with metastatic castration-resistant prostate cancer. Also, another antibody against IGF-1R, figitumumab, resulted in PSA level decreases in the neoadjuvant prostate cancer setting.
Cixutumumab was generally well tolerated. Grade 3 adverse events included hyperglycemia in 8 patients and 0 patients in the cixutumumab and control arms, respectively. There was no association between development of hyperglycemia and PSA response (P = .15).
“Although these results fail to confirm preclinical evidence supporting the combination of castration with IGF-1R inhibition by cixutumumab, it is possible that the primary endpoint of undetectable PSA at 28 weeks does not fully capture cixutumumab efficacy,” concluded the authors.
While preclinical studies showed that time to castration resistance was significantly improved in xenograft models, lowest PSA levels did not differ when cixutumumab was added to castration. Since time to castration resistance is not a validated endpoint for clinical trials in this hormone-sensitive patient population, the 28-week PSA endpoint was chosen as the primary endpoint instead. According to the study authors, the advantage of using this short-term endpoint was to avoid a large allocation of resources and patients to a potentially inactive therapy. It is also possible, according to the authors, that the xenograft models did not fully reflect the biology of human prostate cancer disease.
Patients in this SWOG S0925 trial are still being evaluated for overall survival and other secondary endpoints. “Should the prognostic value of the undetectable PSA model be validated in our trial, future testing of novel therapeutics in the metastatic hormone-sensitive prostate cancer setting will be facilitated with this earlier readout,” stated the authors.