Promising Clinical Activity of Cabozantinib + ADT in Hormone-Naïve Metastatic Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•Cabozantinib is a small-molecule inhibitor of c-MET/VEGFR2 signaling that has yielded improved progression-free survival but not overall survival in patients with metastatic castrate-resistant prostate cancer (mCRPC). Based on preclinical data, the authors hypothesized that cabozantinib could have a role in combination with ADT in the setting of hormone-naïve metastatic prostate cancer (HNMPCa). They enrolled 62 patients who were followed for a median of 31 months. As measured by laboratory markers and imaging, response rates were favorable, as reductions of PSA by ≥90%, alkaline phosphatase by ≥50%, and measurable disease on bone scan were each observed in 80% to 90% of patients. The authors also observed trends in cytokine and angiogenic factors (CAFs) that suggested potential use of these markers in identifying those patients likely to respond favorably to this treatment approach.

•Based on these findings, the authors reasonably conclude that cabozantinib + ADT appears to have activity in the setting of HNMPCa. These data imply that cabozantinib could have a role earlier in the disease course, particularly in combination with epithelial-targeting agents such as abiraterone and docetaxel. Follow-up studies will be necessary to define such a role and the potential use of CAFs to guide therapy.

– Jeffrey J. Tosoian, MD, MPH

PURPOSE

Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa).

PATIENTS AND METHODS

Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation.

RESULTS

Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6-22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1.

CONCLUSIONS

Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.

Clinical Cancer Research

A Phase II Study of Cabozantinib and Androgen Ablation in Patients With Hormone-Naïve Metastatic Prostate Cancer

Clin. Cancer Res 2020 Jan 15;[EPub Ahead of Print], PG Corn, M Zhang, GM Nogueras-Gonzalez, L Xiao, AJ Zurita, SK Subudhi, SM Tu, AM Aparicio, C Coarfa, K Rajapakshe, S Huang, NM Navone, SH Lin, G Wang, S Ramachandran, MA Titus, T Panaretakis, GE Gallick, E Efstathiou, P Troncoso, C Logothetis

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[noirhole]

I participated in the dose escalation trial at MD Anderson under the care of SM Tu who I see is listed in the citations. I saw wonderful response from patients with full skeletal involvement where the drug improved progression down to a few mets. For myself I did not see any bone mets clear up but improve slightly. Since then in the last 5 years I have not had any further bone metastasis so perhaps I did benefit. The trail did leave me with significant neuropathy in my feet. I was pulled out of the trial due to advancement in soft tissue mets as the study was for ADT and I failed lupron after 18 months. I would say if you "light up like a christmas tree" (not medical terminology) on your bone scans this drug may be good option for you. Hopefully my participation in the trial helped dial in the correct dosage for the best benefit with the least side effects. Good luck to you all.