Azenosertib Monotherapy Yields Encouraging Responses in Cyclin E1+ PROC

Results from the ZN-c3-001, MAMMOTH, and DENALI trials demonstrated meaningful ORRs with azenosertib in platinum-resistant ovarian cancer.

Positive updated results for azenosertib monotherapy in patients with Cyclin E1–positive, platinum-resistant ovarian cancer (PROC) from the ZN-c3-001 (NCT04158336), MAMMOTH (NCT05198804), and DENALI (NCT05128825) trials have been released, according to a press release from the developer, Zentalis.1 Additional results from the combination cohorts of MAMMOTH trial were also disclosed.

Results from the trials were shared in a virtual corporate event.2

“We are very pleased with the azenosertib results obtained to date and believe we have a clear path to advancing this product candidate to patients,” Julie Eastland, chief executive officer at Zentalis, stated in the press release.1 “Notably, approximately 50% of patients with PROC [have Cyclin E1–positive disease], and we believe that the therapeutic and commercial opportunity in this population, which tends to be especially treatment-refractory, is substantial.”

The ZN-c3-001 Trial

Azenosertib monotherapy given intermittently elicited an overall response rate (ORR) of 20.7% (95% CI, 11.2%-33.4%) in all patients with PROC and 34.8% (95% CI, 16.4%-57.3%) in patients with Cyclin E1–positive PROC; median duration of response (DOR) was 5.1 months (95% CI, 3.0-5.9) and 5.2 months (95% CI, 2.8-6.9), respectively. For patients given azenosertib continuously, the ORR was 18.8% (95% CI, 2.3%-51.8%) in all patients with PROC and 33.3% (95% CI, 0.8%-90.6%) in patients with Cyclin E1–positive PROC; median DOR was 7.1 months (95% CI, 4.2-not evaluable [NE]) and 4.2 months (95% CI, NE-NE), respectively.

The trial enrolled 274 patients across all tumor types and dosages, 193 of whom received 300 mg or more of azenosertib and were evaluated for safety and anti-tumor activity. Patients were required to have PROC, solid tumors, or uterine serous carcinoma; at least 1 prior line of therapy; and tissue collected for biomarker analysis.

Patients either received azenosertib continuously at 300 mg, 350 mg, 400 mg, or 450 mg, or intermittently in a 5:2 or 4:3 schedule at 350 mg once a day and 175 mg twice a day, 400 mg, 450 mg, or 500 mg.

The median age in the PROC cohort (n = 69) was 66 years (range, 48-83); 72% had an ECOG performance status of 1; the median number of prior lines of treatment was 5 (range, 1-19), with the most common 4 or more (68%). The most common prior therapies were VEGF inhibitors (87%), PARP inhibitors (67%), and PD-1/PD-L1 therapy (17%); and 38% of patients had Cyclin E1–positive status.

Across all tumor types evaluated, the most common treatment-related adverse events (TRAEs) of any grade were nausea (60.6%), fatigue (58.5%), diarrhea (51.8%), and anemia (30.1%); of grade 3 or higher, the most common TRAEs were fatigue (13.5%), neutropenia (13.0%), anemia (11.4%), and thrombocytopenia (10.9%). TRAEs led to dose reduction in 39.4%, dose interruption in 40.4%, treatment discontinuation in 5.2%, and death in 0.5%.

The MAMMOTH Trial

Patients who received 300 mg of azenosertib monotherapy (n = 25) achieved an ORR of 20.0% (95% CI, 6.8%-40.7%) in all patients with PROC and 21.4% (95% CI, 4.7%-50.8%) in those with Cyclin E1–positive PROC; the median DOR was 4.9 months (95% CI, 2.8-NE) and 4.9 months (95% CI, 3.0-NE), respectively. In those who received 400 mg of azenosertib (n = 36), all patients with PROC had an ORR of 22.2% (95% CI, 10.1%-39.2%) vs 31.3% (95% CI, 11.0%-58.7%) in patients with Cyclin E1–positive PROC; median DOR was 5.5 months (95% CI, 2.7-NE) and 4.2 months (95% CI, 3.0-NE). Both dosages were administered on a 5:2 schedule.

A total of 117 patients who had received between 1 and 5 prior lines of therapy, were platinum resistant and progressed while receiving a PARP inhibitor, and had sufficient tissue for biomarker analysis were enrolled. The azenosertib monotherapy arm of the trial had a total of 61 patients, and the end points were ORR, DOR, progression-free survival (PFS), and safety and tolerability.

The median age of patients who received 300 mg was 71.0 years (range, 45-80) and 63.0 years (range, 31-84) for patients who received 400 mg; 72% and 56%, respectively, had an ECOG performance status of 1; 60% and 56% received 1 to 3 prior therapies; 100% and 100% received PARP inhibitors; 96% and 94% received bevacizumab (Avastin); and 52% and 44% had Cyclin E1–positive disease.

The most common TRAEs of any grade in the 300 mg and 400 mg cohorts were nausea (60.0% and 52.8%, respectively), diarrhea (52.0% and 47.2%), anemia (40.0% and 38.9%), and thrombocytopenia (32.0% and 36.1%). Of grade 3 or higher, they were anemia (12.0% and 16.7%), neutropenia (12.0% and 13.9%), thrombocytopenia (8.0% and 11.1%), and diarrhea (0% and 11.1%). TRAEs led to dose reduction in 44.0% and 41.7% of patients, respectively, dose interruption in 44.0% and 38.9%, treatment discontinuation in 16.0% and 5.6%, and death in 0.0% and 2.8%.

The DENALI Trial

In the overall trial population, azenosertib monotherapy yielded an ORR of 19.4% (95% CI, 11.9%-28.9%) in response evaluable patients and 17.6% (95% CI, 10.8%-26.5%) in the intent-to-treat (ITT) population. Response evaluable patients who had Cyclin E1–positive disease experienced an ORR of 34.9% (95% CI, 21.0%-50.9%) and 31.3% (95% CI, 18.7%-46.3%) for patients in the ITT population. Those with non-Cyclin E1 immunohistochemistry–positive status had an ORR of 6.0% (95% CI, 1.3%-16.6%) in the response evaluable population and 5.6% (95% CI, 1.2%-15.4%) in the ITT population.

In patients with Cyclin E1–positive disease, the median DOR was 5.5 months (95% CI, 2.7-NE), and median PFS was 4.1 months (95% CI, 2.8-6.8).

A total of 102 patients with PROC who received 1 to 5 prior lines of therapy and had tissue for biomarker assessment were administered 400 mg of azenosertib monotherapy on a 5:2 schedule in part 1b of the DENALI trial. Trial end points were ORR, DOR, PFS, and safety and tolerability.

The median age of patients was 66 years (range, 34-82), 52% of patients had an ECOG performance status of 0, the most common number of prior therapies was 3 (31%), 91% had prior treatment with bevacizumab, 57% received a prior PARP inhibitor, and 47% had Cyclin E1–positive disease.

The most common TRAEs of any grade were nausea (65.7%), fatigue (59.8%), diarrhea (50.0%), thrombocytopenia (34.3%), and anemia (30.4%). Of grade 3 or higher, the most common were fatigue (15.7%), thrombocytopenia (11.8%), neutropenia (10.8%), anemia (10.8%), and diarrhea (6.9%). TRAEs led to dose reduction in 42.2% of patients, dose interruption in 58.8%, treatment discontinuation in 21.6%, and death in 2.0%.

References

1. Zentalis Pharmaceuticals shares updated clinical data demonstrating meaningful azenosertib activity in cyclin E1+, platinum-resistant ovarian cancer. News release. Zentalis Pharmaceuticals. January 29, 2025. Accessed January 29, 2025. https://tinyurl.com/2fjvu5rv
2. Corporate Event. Zentalis. January 29, 2025. Accessed January 29, 2025. https://tinyurl.com/3scayxrn