Onvansertib/Abiraterone Stabilizes PSA in 75 Percent of Patients With mCRPC

The combination of onvansertib (PCM-075) with abiraterone acetate (Zytiga) decreased the prostate-specific antigen (PSA) levels in most of the evaluable patients treated in a phase II study (NCT03414034), which used the combination in adult patients with metastatic castration-resistance prostate cancer (mCRPC), according to a press release from onvansertib developer, Trovagene, Inc.¹

The results presented at the European Multidisciplinary Congress on Urological Cancers (EMUC) show that after 3 months of treatment with onvansertib plus abiraterone acetate, 60% of patients has a partial response (PR) or stable disease. A decrease in PSA was seen after just 1 cycle of treatment with onvansertib in 72% of the patients. The 1 patient who had a PR to the combination was ART-V7-positive, showed no increase in circulating tumor cell counts, and had a decrease in PSA.²

One hundred percent of the participants who originally tested positive for highly aggressive, resistant AR-V7 variant (n = 5) showed decreases in PSA levels after 1 cycle of onvansertib treatment. Additionally, disease control was detected in 75% of patients evaluable for efficacy. The study met its primary endpoint of PSA stabilization.

In a non-randomized fashion, patients were divided into 2 arms . In arm A, patients were treated on day 1 through 5 of a 14-day cycle with onvansertib/abiraterone acetate 24mg/m^2. In arm B, patients received the same dosage of the combination on days 1 through 5 of a 21-day cycle. Participants in both arms also received abiraterone and prednisone.

Onvansertib plus abiraterone acetate was considered safe and well-tolerated in all patients enrolled in the study, and the adverse events (AEs) that patients experienced were as expected. The most common AEs were neutropenia, thrombocytopenia and white blood cell count decrease.

In addition to evaluating PSA stabilization, the study had several secondary endpoints, including, percentage change from baseline in PSA at 12 weeks, maximal percentage change from baseline in PSA, time to PSA progression, time to radiographic progression, radiographic response, the number of participants with dose-limiting toxicity, and the number of patients with AEs.

The overall purpose of the study was to determine the safety and efficacy of the combination in this patient population. According to a statement from Mark Erlander, MD, chief scientific officer, Trovagene Oncology, the data from this study show promise regarding efficacy.

"The new data shared today builds upon the encouraging clinical response observed to date when onvansertib is added to treatment in patients who have developed resistance to androgen receptor signaling inhibitor, Zytiga®. Of particular significance are the positive results we are observing in patients who harbor the highly aggressive, resistant variant of the androgen receptor. These patients are resistant to ARS inhibitors including Zytiga® and Xtandi® (enzalutamide - Pfizer) and their therapeutic options are not only limited but often ineffective,” said Erlander.

The key inclusion criteria were patients with a histologically confirmed mCRPC with rising PSA and/or radiographic progression. All patients must have either undergone surgical castration or continue on a gonadotropin-releasing hormone agonist/antagonist throughout the study. Patients also required an Eastern Cooperative Oncology Group performance score of 0 to 1, as well as, absolute neutrophil count ≥ 1.0 x 109/L, a platelet count ≥ 100 x 109/L, serum creatinine ≤ 2 x the upper limit of normal (ULN), a total serum bilirubin ≤ 1.5 x ULN, and an aspartate aminotransferase and alanine aminotransferase ≤ 3 x ULN or ≤ 5.0 x ULN  in the case of hepatic metastasis.

Individuals who were previously treated with chemotherapy, investigational agents, immunotherapy, hormonal therapy, or with enzalutamide other experimental therapies were excluded from the study. Having had major surgery within 28 days of the study start date also excluded some individuals from the study. Patients with rapidly progressive symptoms of mCRPC were excluded as well.

Onvansertib, a third-generation first-in-class, adenosine triphosphate inhibitor is showing promise when combined with chemotherapies and targeted agents. In a phase I/IIl involving patients with KRAS-mutated mCRPC, onvansertib is being combined with leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan or FOLFRI and bevacizumab (Avastin) (NCT03829410). The drug is also showing promise in other malignancies, like the phase Ib/II in combination onvansertib plus low-dose cytarabine or decitabine in patients with relapsed or refractory AML, (NCT03303339).

“We believe the addition of onvansertib has the potential to deliver transformative benefit to patients with mCRPC by extending the duration of response to treatment with ARS inhibitors,” Erlander mentioned in his statement to the press.

References

1. Trovagene Presents Positive Data in Metastatic Prostate Cancer Phase 2 Trial Showing Clinical Response in Patients Resistant to Zytiga® [press release]. San Diego, California: Trovagene, Inc.; November 14, 2019.https://yhoo.it/34nct6X. Accessed November 26, 2019.
2. Einstein DJ, Choudhury A, Saylor P, et al. A phase 2 study of the combination of PLK1 inhibitor, onvansertib, with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer. Presented at the 2019 European Multidisciplinary Congress on Urological Cancers; November 14—17, 2019; Vienna, Austria. Poster 042.