Cabozantinib Plus ADT Shows Promise in Hormone-Naive Metastatic Prostate Cancer

Paul G. Corn, MD, PhD

Paul G. Corn, MD, PhD

Combining cabozantinib (Cabometyx) plus androgen-deprivation therapy (ADT) as first-line therapy in patients with hormone-naïve metastatic prostate cancer yields promising clinical activity, according to the new single-arm phase II study, which was published inClinical Cancer Research.

“We observed promising anti-disease activity and identified blood and tissue-based markers to potentially identify patient subsets most likely to benefit,” wrote the authors, led by Paul G. Corn, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. “These data suggest that moving cabozantinib earlier in the disease course with more potent epithelial-targeting agents such as abiraterone or docetaxel could serve as a foundation to explore rational therapy combinations.”

Median follow-up was 31.2 months. The median PFS for the entire cohort was 16.1 months (95% CI, 14.6—22.7 months). The high-volume group had a median PFS of 16.1 months (95% CI, 13.3–21.5 months), compared with 20.2 months for the low-volume group (95% CI, 15.1–NA months; Hazard Ratio [HR] 1.56; 95% CI, 0.66–3.66,P= 0.31). As of publication, 18 patients (29%) had died; the median OS had not been reached.

Additional findings of note include that 83% of patients experienced a reduction in PSA of at least 90%. Also, decreases in bone-specific alkaline phosphatase of at least 50% and urine N-telopeptides of at least 50% were observed in 87% and 86% of patients, respectively. A large majority of patients displayed responses in bone scans (81%) and measurable disease (90%).

There were no grade 4 adverse events (AEs) and no treatment-related deaths. The most common grade 3 AEs were hypertension in 12 patients (19%), diarrhea in 4 patients (6%), and thromboembolic events in 4 patients(6%). Of the 9 patients who discontinued treatment due to AEs, the most common reason was for stroke (n = 2, 3%). One patient each experienced transient-ischemic attack, pulmonary embolism, proteinuria, peripheral neuropathy, and several other conditions.

Corn et al contextualized their results by noting that previous MD Anderson data showed that the median time to castrate-resistant progression in patients with high-volume disease treated with ADT alone was 11.2 months. “Thus, the mPFS of 16.1 months we observed in high-volume patients in our study suggests promising anti-disease activity … This clinical efficacy signal supports the hypothesis that therapeutic strategies that target the tumor stroma may improve patient outcomes,” they wrote. “Our data further suggest that applying stromal targeting therapies earlier in the disease course may potentially enhance efficacy beyond what has been observed in heavily pretreated patients with castrate-resistant disease, the patient group most commonly studied in clinical trials with these agents.”

Eligible patients had pathologically confirmed adenocarcinoma without small cell elements and metastatic disease assessed by bone scan, CT scan and/or MRI, as well as an ECOG performance status of 0, 1, or 2. ADT consisted of LHRH agonist or antagonist therapy, and anti-androgens could be used up to 4 weeks at the beginning of ADT treatment.

The starting study dose of cabozantinib was 60 mg daily. The original trial protocol permitted dose reductions to 40 and 20 mg daily; this was later amended to permit dose interruptions up to 3 days per week and the use of 2 weeks on, 1 week off as an alternative schedule. Treatment continued until disease progression, excessive toxicity or radiation treatment to more than one site.

The primary endpoint was castrate-resistant PFS. Secondary endpoints included radiographic responses, OS, and biomarker modulation in blood and tumor tissues.

Trial enrollment consisted of 62 patients. Of these, 46 patients (74%) hadde novometastatic disease and 54 patients (87%) had high-volume disease. At data cutoff, nearly all patients had discontinued the study regimen (n = 57, 92%) and a sizeable majority (n = 50, 81%) had developed castrate-resistant progression.

Corn et al found the median duration of cabozantinib treatment to be 13.8 months (95% CI, 10.5—15.7 months). Fifty-three patients (85%) required at least one dose reduction. Of these, 42 patients (68%) were reduced to 40 mg, while 11 patients (18%) were further reduced to 20 mg. The median time to the first dose reduction was 2.1 months (range, 0.7–11.3 months), and the median time to the second dose reduction was 5.7 months (range, 2.1–11.7). Nearly half the patients (n = 27, 44%) received an alternate dosing schedule, with the 5-day on, 2-day off schedule being most common (n = 17, 27%).

Corn et al also noted the limitation of their single-arm trial design, which “confounds the ability to distinguish whether baseline clinical features or potential biomarkers are predictive, prognostic, or both.” They advocate for future randomized trials that make use of image-guided and liquid biopsies to explore whether therapeutic strategies that inhibit c-MET/VEGF2 signaling can be successful in patients with hormone-naïve metastatic prostate cancer.

Reference:

Corn PG, Zhang M, Nogueras-Gonzalez GM, et al. A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer.Clin Cancer Res. Published online January 15, 2020.