NEW YORK – Trovagene presented data from an ongoing Phase II trial of a metastatic castration-resistant prostate cancer regimen containing its investigational agent onvansertib, abiraterone acetate (Janssen's Zytiga), and prednisone.
According to data presented at the Asia-Pacific Prostate Cancer Conference in Melbourne, Australia this week, onvansertib is efficacious in patients who have become resistant to the androgen receptor signaling (ARS) inhibitor abiraterone acetate, as well as patients who have androgen receptor variant 7 (AR-V7) tumors, a particularly fast-growing and hard to treat form of the disease.
"We have discovered that adding onvansertib to daily ARS inhibitor therapy changes the trajectory of resistance in patients harboring AR-V7, as demonstrated by the immediate decrease in serum PSA levels in patients showing initial signs of resistance to [abiraterone acetate]," Trovagene CSO Mark Erlander said in a statement. "The inhibition of the PLK1 enzyme by onvansertib appears to enhance the efficacy of [abiraterone acetate] by repressing the ARS pathway, which is consistent with preclinical data."
The Phase II study aims to ultimately enroll 64 patients. Researchers analyze patients' circulating tumor cells to establish AR-V7 status at baseline using a blood test from Epic Sciences and Johns Hopkins University.
Studies previously have suggested that patients with constituently active AR-V7 develop resistance to ARS inhibitors and other prostate cancer treatments. Furthermore, a number of clinical trials have shown that AR-V7-negative patients tend to respond to ARS inhibitors, while AR-V7-positive patients don't respond well. In addition to analysis of CTCs, researchers are also using Guardant Health's liquid biopsy test to gauge response biomarkers in circulating tumor DNA.
The study includes two arms exploring different dosing regimens of onvansertib and involving 24 patients in total, of whom, a dozen have completed three months of treatment, 10 are still on treatment, and five are AR-V7 positive. Four patients who tested positive for the androgen receptor splice variant had an "immediate decrease" in serum prostate specific antigen levels when treated with onvansertib, according to Trovagene.
Two of these patients have experienced disease control, the company added. One AR-V7-positive patient experienced more than a five-fold rise in PSA when receiving abiraterone acetate, but after entering this study and receiving onvansertib, the patient's PSA levels quickly decreased. Patients treated to date also have not experienced any unexpected, off-target toxicities in this study.
Patients with castration-resistant prostate cancer live on average between 15 and 36 months after diagnosis. They typically receive ARS inhibitors, such as abiraterone acetate or enzalutamide (Pfizer's Xtandi), but tend to develop resistance to these drugs in nine to 15 months. For the 30 percent of patients with AR-V7-driven resistance, the survival is even shorter, and in the absence of targeted treatment options, patients receive more toxic chemotherapies.