Onvansertib Combo Achieves Disease Control, Overcomes Abiraterone Resistance in mCRPC

David Einstein, MD

The combination of onvansertib (PCM-075) plus abiraterone acetate (Zytiga) and prednisone achieved disease control in patients with metastatic castration-resistant prostate cancer who had initial resistance to abiraterone, achieving the primary end point of a phase 2 trial (NCT03414034).¹

Data from the trial presented during the 27th Annual Prostate Cancer Foundation (PCF) Scientific Retreat showed that 31% of evaluable patients (n = 8/26) achieved disease control with the onvansertib combination, which was defined by a lack of prostate-specific antigen progression following 12 weeks of treatment. Moreover, a little more than half, or 54% (n = 14/26), achieved stable disease (SD) following 12 weeks of treatment, and 31% (n = 8/36) had durable SD of over 7 months.

Additionally, among 8 participants who harbored androgen receptor alterations linked with abiraterone resistance, 3 patients achieved disease control at 12 weeks with the onvansertib combination, 4 patients experienced SD at 12 weeks, and 3 reported durable SD.

“There is a pressing unmet need for therapies that can address resistance to abiraterone and other androgen receptor signaling inhibitors (ARSi),” said David Einstein, MD, attending physician at Beth Israel Deaconness Medical Center and principal investigator of the onvansertib phase 2 trial.¹ “Data presented at the PCF retreat demonstrate the potential of onvansertib to address this need, as we are seeing clinically meaningful rates of disease control, some quite durable, in patients with known mechanisms of ARSi resistance.”

In the open-label phase 2 trial, investigators set out to evaluate oral onvansertib plus abiraterone and prednisone in patients with mCRPC who showcased early signs of disease progression while on treatment with abiraterone/prednisone.

To be eligible for inclusion, patients had to be 18 years of age or older, have the ability to swallow the study drug as a whole tablet, and have histologically confirmed prostate adenocarcinoma without significant small-cell/neuroendocrine or other variant histologies, with rising PSA and/or radiographic progression in the setting of castration-level testosterone indicative of metastatic disease.²

Patients also had to be mildly symptomatic or asymptomatic, be receiving abiraterone/prednisone for their disease, and have 2 rising PSA values separated by at least 1 week, 1 showing a rise of at least 0.3 ng/mL and 1 confirmatory value not demonstrating a decline while receiving abiraterone treatment. They also needed to have an ECOG performance status of 0 or 1 and acceptable bone marrow and organ function.

They could not participate if they underwent a major surgical procedure within 28 days before starting the study or had not yet recovered from adverse effects associated with such a procedure. If they had rapidly progressive symptoms, acute neurological dysfunction from bone metastasis, or received previous treatment with enzalutamide (Xtandi) or other therapies targeting the androgen receptor, they were excluded from the analysis.

The primary efficacy end point of the trial was the proportion of patients who achieved disease control following 12 weeks of treatment; this was defined as a lack of PSA, radiographic, or symptomatic progression.

Key secondary end points included percentage change from baseline in PSA at 12 weeks, maximal percentage change from baseline in PSA, absolute change in baseline with regard to PSA response, time to PSA progression in accordance with Prostate Cancer Working Group 3 (PCWG3) criteria, time to radiographic progression per PCWG3 criteria, radiographic response per RECIST v1.1 criteria, percentage of patients adherent to the study treatment with a lack of PSA progression per PCWG3 criteria after 12 weeks, and safety.

In the trial, onvansertib was evaluated at 3 different doses: 24 mg/m² (arm A) 18 mg/m² (arm B) and 12 mg/m² (arm C). Oral onvansertib was administered on day 1 of each treatment cycle once daily for the duration of 5 days, day 1 through day 5, out of a 21-day treatment cycle in arms A and B. Abiraterone and prednisone was administered on day 1 and uninterrupted throughout each cycle. In arm C, onvansertib was given in the same schedule, but for a longer duration of 14 days. Arm A was discontinued.

Additional results from a biomarker analysis revealed the identification of a gene signature that is linked with onvansertib/abiraterone synergy in prostate cancer cells that was found to be significantly enriched in the subgroup of patients with the basal molecular tumor subtype of the disease.

The safety lead-in of the trial was completed across arms A, B, and C. Results indicated that the combination was safe across all the different doses and scheduled evaluated.

“We are very pleased with the progress and results of the trial to date,” said Mark Erlander, PhD, chief executive officer of Cardiff Oncology.¹ “In particular, we are encouraged by the identification of a biomarker that could readily select for [patients who are] abiraterone resistant and are most likely to benefit from the addition of onvansertib to their regimen.”

References

1. Cardiff Oncology presents positive efficacy and biomarker data from mCRPC trial demonstrating ability of onvansertib to overcome Zytiga resistance. News release. Cardiff Oncology, Inc. October 20, 2020. Accessed October 20, 2020. https://bit.ly/3jeF0lS.
2. Onvansertib in combination with abiraterone and prednisone in adult patients with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated September 30, 2020. Accessed October 20, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03414034.