Abiraterone/prednisone can increase survival in prostate cancer; however, most patients develop resistance between 9 and 16 months after starting treatment.
The addition of onvansertib to abiraterone acetate (Zytiga) and prednisone yielded clinically meaningful activity in patients with metastatic castration-resistant prostate cancer (mCRPC) and early signs of resistance to abiraterone.1
Data from a phase 2 trial presented during the 2021 Genitourinary Cancers Symposium showed that over one-third (35%) of patients across the 3 onvansertib doses had disease control at 12 weeks, the primary end point of the study. Further, one of the three onvansertib doses led to 63% of patients achieving disease control at 12 weeks.
Onvansertib is an oral PLK1 inhibitor. Research has shown that PLK1 is overexpressed in prostate tumors and is associated with higher grade prostate cancers.
The open-label, phase 2 study is exploring onvansertib in patients with mCRPC receiving abiraterone/prednisone and showing early signs of progressive disease. The study defined initial progressive disease as tests showing 2 rising PSA values separated by ≥1 week of the patients having minimal or no symptoms.
As of January 11, 2021, 51 patients had been treated across the study’s 3 dosing schedules, which comprised onvansertib at 24 mg/m2 (arm A; days 1-5 of 21-day cycles), 18 mg/m2 (arm B; days 1-5 of 14-day cycle), or 12 mg/m2 (arm C; days 1-14 of 21-day cycles).The results shared during the symposium included 24, 17, and 10, patients in arms A, B, and C, respectively.
Across all 51 treated patients, the median age was 72 years (range, 51-87), 86% of patients were White, and 84% had an ECOG performance status of 0. The median number of years since diagnosis was 4 (range, 1-28), the median baseline PSA was 11.4 ng/mL (range, 0.6-515), 57% were grade groups 4 and 5, and 37% had de novo metastatic disease. Visceral metastasis was present in 35% of cases, with bone metastasis occurring in 82%.
Across the 3 cohorts, there were 37 patients in the efficacy evaluable population, which included patients who completed at least 12 weeks of treatment or had disease progression within 12 weeks. Thirteen (35%) of these 37 patients achieved the primary end point of disease control at 12 weeks
In arm C, 5 (63%) of 8 evaluable patients had disease control at 12 weeks. This compared with 5 (29%) of 17 evaluable patients in arm A and 3 (25%) of 12 evaluable patients in arm B. Radiographic stable disease at 12 weeks was achieved by 6, 9, and 5 patients in arms C, A, and B, respectively. Three patients in arm C had a response lasting ≥6 months, compared with 5 patients each in arms A and B.
Over half (53%; n = 19) of the efficacy evaluable patients had 1 or more androgen receptor alterations associated with resistance to abiraterone. At 12 weeks, 5 of these patients achieved disease control and 8 had radiographic stable disease.
Safety data across all 51 treated patients showed that the combination of onvansertib and abiraterone was tolerable across the 3 dosing schedules of the PLK1 inhibitor. Grade 3 adverse events (AEs) occurring across the 3 dosing schedules were anemia (n = 1), neutropenia (n = 7), hypophosphatemia (n = 4), white blood cell (WBC) decrease (n = 3), and hypokalemia (n = 1). Grade 4 AEs across all doses included 2 cases of WBC decrease.
"The preliminary data presented at ASCO-GU support a clinically meaningful onvansertib exposure effect," principal investigator David Einstein, MD, attending physician at Beth Israel Deaconess Medical Center, stated in a press release. "In the first 8 patients treated to-date on Arm C, we are excited to see an increase in DCR with greater time on onvansertib, without excessive toxicity. Together with the clinically meaningful rates of disease control, and duration of disease control, we are seeing across all cohorts, these data demonstrate onvansertib's potential to address a critical unmet need for patients with abiraterone-resistant mCRPC."
1. Einstein DJ, Choudhury AD, Saylor PJ, et al. A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 39, 2021 (suppl 6; abstr TPS186). doi 10.1200/JCO.2021.39.6_suppl.TPS186