Abemaciclib trial misses end point, but supports targeting CDK4/6 in mCRPC

Findings from the phase 2 CYCLONE 1 trial (NCT04408924) presented during the 2023 AACR Annual Meeting showed that abemaciclib (Verzenio) did not achieve the primary end point of overall response rate (ORR) in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC); however, the CDK4/6 inhibitor did demonstrate clinical activity in this setting.¹

The phase 2/3 CYCLONE 2 (NCT03706365) and the phase 3 CYCLONE 3 (NCT05288166) trials are underway, examining abemaciclib in combination with abiraterone acetate and prednisone for patients with treatment-naïve mCRPC and high-risk metastatic hormone-sensitive prostate cancer, respectively.

At a median follow-up of approximately 8.5 months, the CYCLONE 1 results showed that patients who received the CDK4/6 inhibitor (n = 44) experienced an ORR of 6.8% (95% CI, 0.0%-14.3%), defined as a confirmed soft tissue response without concurrent bone progression.

The disease control rate (DCR) was 45.5% (95% CI, 30.7%-60.2%), with 38.6% of patients achieving stable disease (SD). SD persisted for at least 6 months in 13.6% of patients. All responses were partial, and 20.5% of patients were not evaluable (NE) for response.

CYCLONE 1 was a single-arm trial that evaluated the safety and efficacy of abemaciclib monotherapy in patients with mCRPC with an ECOG performance status of 0 or 1 who had received prior treatment with at least 1 novel hormonal agent and 2 prior taxanes for metastatic prostate cancer. Patients who had previously received abemaciclib or another CDK4/6 inhibitor, those with brain metastases, and those who have received more than 3 therapy regimens for mCRPC were excluded from the study.^1,2

Oral abemaciclib was given at a dose of 200 mg twice daily as part of a continuous 28-day dosing schedule until radiographic or symptomatic progression or unacceptable toxicity. The median number of treatment cycles was 3 (range, 1-13).

In terms of the primary end point, a target ORR of at least 12.5% was deemed suitable to support further evaluation of abemaciclib monotherapy in the refractory mCRPC setting. Secondary end points included radiographic progression-free survival (rPFS), DCR, overall survival (OS), safety, and time to prostate-specific antigen (PSA) progression.

The median age of patients enrolled on the trial was 68 years (range, 48-94). Most patients had an ECOG performance status of 1 (75%), at least 3 metastatic sites (93.0%), radiographic progression at trial entry (90.9%), and had a nonvisceral disease site (53.5%). Visceral metastasis was reported in 46.5% of patients, including 27.9% with liver metastasis.

The median time from development of mCRPC to study entry was 2.1 years. The median number of prior systemic regimens for mCRPC was 3.

Most patients (56.8%) underwent at least 3 lines of prior therapy, with 43.2% being treated with 2 or fewer. The most common prior chemotherapy agents included docetaxel (100%), cabazitaxel (90.9%), carboplatin (4.5%), and paclitaxel (2.3%). Previous novel hormonal agents included abiraterone acetate (Zytiga; 54.5%), enzalutamide (Xtandi; 54.5%), apalutamide (Erleada; 4.5%), and darolutamide (Nubeqa; 2.3%). Prior immunotherapy approaches, which 13.6% of patients had overall, included pembrolizumab (Keytruda; 6.8%), atezolizumab (Tecentriq; 2.3%), durvalumab (Imfinzi; 2.3%), ipilimumab (Yervoy; 2.3%), and nivolumab (Opdivo; 2.3%).

At the time of data cutoff, 7% of patients remained on treatment. Among the 41 patients who ceased treatment, reasons for discontinuation included progressive disease (68%), adverse effects (14%), physician’s decision (5%), withdrawal (5%), and death (2%).

Additional data regarding survival outcomes showed that the median rPFS was 2.7 months (95% CI, 1.9-3.7), with a 6-month rPFS rate of 24.9% (95% CI 12.4%-39.5%) and 75% of patients experienced an rPFS event. The median OS was 7.6 months (95% CI 5.6-not estimable [NE]), with 43.2% of patients experiencing an OS event. The duration of response ranged from 3.7 months to 5.6 months.

The median time to PSA progression was 6.5 months (95% CI, 3.2-NE), with 29.5% of patients experiencing a PSA progression event. Any PSA decrease was reported in 27.3% of patients and 4.6% experienced a confirmed PSA response rate of at least 50%. The median time to systemic progression was 4.1 months (95% CI, 3.7-NE).

The safety profile of abemaciclib was consistent with what has been previously observed in patients with breast cancer, investigators noted. The most common any-grade treatment-related adverse effects (TRAEs) of any grade included diarrhea (79.5%), decreased appetite (52.3%), and fatigue (50%). Most of these events were grade 1 or 2 in severity.

Grade 3 TRAEs consisted of neutropenia (22.7%), anemia (6.8%), fatigue (6.8%) and diarrhea (6.8%). Grade 4 or 5 TRAEs were not reported and the discontinuation rate due to AEs was 13.6%.

Treatment-emergent adverse events (TEAEs) of any grade included diarrhea (81.8%), fatigue (63.6%), decreased appetite (54.5%), and nausea (47.7%). Grade 3 TEAEs consisted of neutropenia (25.0%), fatigue (11.4%), diarrhea (9.1%), and thrombocytopenia (4.5%).

Study authors concluded that the single-agent activity displayed by abemaciclib in CYCLONE 1 validates CDK4/6 as a therapeutic target in advanced prostate cancer. The phase 2/3 CYCLONE 2 (NCT03706365) and the phase 3 CYCLONE 3 (NCT05288166) trials are underway, examining abemaciclib in combination with abiraterone acetate and prednisone for patients with treatment-naïve mCRPC and high-risk metastatic hormone-sensitive prostate cancer, respectively.

References

1. Agarwal N, Gauna DC, Gordoa TA, et al. CYCLONE 1: abemaciclib in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Cancer Res. 2023;83(suppl 8):CT159. doi:10.1158/1538-7445.AM2023-CT159

2. Abemaciclib (LY2835219) in men with heavily treated metastatic castration-resistant prostate cancer (CYCLONE 1). ClinicalTrials.gov. Updated February 14, 2023. Accessed April 17, 2023. https://clinicaltrials.gov/ct2/show/NCT04408924