PLK1 Inhibitor, Abiraterone Combo Shows Preliminary Efficacy and Safety in mCRPC

David J. Einstein, MD

In a phase 2 trial (NCT03414034), onvansertib, a polo-like kinase 1 (PLK1) inhibitor, combined with abiraterone acetate (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have early abiraterone resistance, demonstrated a decent safety profile across 3 dosing schedules and efficacy in the evaluable arms.

“PLK1 is a regulator of the G2/M checkpoint and onvansertib is a highly selective and short half-life inhibitor of PLK1. So, interestingly, looking at preclinical cell lines and xenograft models, there appears to be a synergy between PLK1 inhibition and abiraterone,” David J. Einstein, MD, said in his presentation of the study authors’ poster during the 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat. “That does not seem to be dependent on AR [androgen receptor] effects, so enzalutamide [Xtandi] does not recapitulate that synergy. We do see this synergy in AR-negative prostate lines and even non-prostate cancer cell lines.”

This combination achieved its primary end point of prostate specific antigen (PSA) stabilization in 8 (31%) of the evaluable patients across arms A and B (n = 26) in a preliminary evaluation of efficacy. Stable disease was observed in 14 (54%) patients at 12 weeks and durable response of over 7 months was seen in 8 (31%) patients.

Of the 8 patients with AR alterations associated with abiraterone resistance, 3 achieved disease control and 4 had stable disease. The AR mechanisms of resistance to abiraterone on this study consisted of AR-V7, the AR T878A mutation, and amplification of AR.

Additionally, onvansertib plus abiraterone induced circulating tumor cell (CTC) conversion from unfavorable to favorable, which also correlated with durable response in patients. Unfavorable CTC count was defined as 5 or more CTCs/7.5 mL of blood and favorable was less than 5 CTCs/7.5 mL of blood. The CTC count, which is a prognostic factor for survival in this population, was unfavorable in 27 (73%) patients at baseline. Of the 10 patients re-evaluated at 12 weeks, 5 had a CTC decrease of 80% or more and 4 had converted from unfavorable to favorable, which included 3 with no detectable CTCs.

For all 3 arms of the trial, there was a safety lead-in; arm A (n = 24) at 24 mg/m2 of onvansertib on days 1 through 5 of a 21-day cycle; arm B (n = 32) at 18 mg/m2 on days 1 through 5 of a 14-day cycle; and arm C (n = 32) at 12 mg/m2 on days 1 through 14 of a 21-day cycle. Treatment was given for 12 weeks, or 4 cycles in arm A and C and 6 cycles in arm B.

The most frequent grade 3/4 adverse events were hematologic—which was expected due to the mechanism of action of onvansertib—such as anemia, neutropenia, thrombocytopenia, and white blood cell decrease. These events were reversible and managed with dose delay, dose reduction, and/or growth factor support.

Investigators identified a synergistic gene signature, which was mostly made up of mitosis-related genes, that is enriched in patients with a basal molecular subtype compared with other subtypes (P <.001). They suggested that patients with this subtype may have a greater likelihood of response to the combination.

Patients with mCRPC on this trial had initial signs of abiraterone resistance of 2 rising PSAs¾1 rise of 0.3 ng/mL or more separated by 1 week. Patients were not considered eligible if they had prior treatment with enzalutamide or apalutamide (Erleada); if they had rapidly progressing disease; or significant symptoms related to disease progression.

Disease control was evaluated as PSA decline or stabilization¾defined as PSA rise of less than 25% over baseline¾after 12 weeks of treatment with the combination was the primary end point of the trial. The secondary end points were radiographic response per RECIST v1.1, time to PSA progression, and time to radiographic response. The investigators were also looking at CTCs and circulating tumor DNA to identify response biomarkers.

For baseline characteristics, 39 patients total were included. The median age was 72 years old (range, 54-87) and there were 5 patients who were not white. Most had an ECOG performance status of 0 (87%) and the rest had a status of 1. Nine (23%) patients had AR-V7 at baseline. The median CTC count/mL of blood was 2.2 at baseline (range, 0-87) and the median baseline PSA was 12.5 ng/mL (range, 0.6-224).

“In sum, onvansertib plus abiraterone seemed to be safe and demonstrated some preliminary efficacy data with about 30% of patients achieving disease control 3 months into therapy and some patients having durable stable disease, especially in association with decreases in CTC,” concluded Einstein, instructor of medicine at Harvard Medical School and attending physician at the Beth Israel Deaconess Medical Center. “We’ll be doing some more work looking at predictors of response and trying to clarify the mechanism of action, which seems relevant to mitosis.”

_Reference:

_{Einstein DJ, Choudhury A, Saylor P, et al. A phase 2 study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with abiraterone in patients with abiraterone (Abi)-resistant metastatic castration-resistant prostate cancer (mCRPC). Presented at: 27th Annual Prostate Cancer Foundation Virtual Scientific Retreat; October 20-23, 2020; Virtual. https://bit.ly/3dQbTnW}