COPENHAGEN, Denmark — Alisertib monotherapy may be effective in certain patients with clinical or pathologically defined neuroendocrine prostate cancer, according to phase 2 study results presented at the European Society for Medical Oncology Congress.
Use of molecular, pathologic or clinical features — as well as better characterization of patients who demonstrated exceptional response — could better identify patients most likely to derive benefit.
“We demonstrated the feasibility of conducting a multicenter trial enrolling this aggressive subgroup of patients,” Himisha Beltran, MD, medical oncologist at Weill Cornell Medicine, said during a presentation. “Although the trial did not meet its primary endpoint, exceptional and long-term responders were identified, all of whom had neuroendocrine histology.”
N-myc gene amplification and Aurora kinase A combine to drive neuroendocrine prostate cancer, an aggressive androgen-independent subtype of castration-resistant prostate cancer.
The disease is associated with androgen receptor independence, low- or nonrising PSA progression, aggressive disease and distinct molecular features, according to study background. Median OS for these patients is approximately 7 months.
Preclinical studies showed alisertib (MLN8237, Takeda/Millennium) — an oral, selective inhibitor of Aurora kinase A — inhibited the interaction between Aurora kinase A and N-myc, thereby suppressing neuroendocrine prostate cancer signaling and tumor growth.
Beltran and colleagues conducted a multicenter study to investigate the efficacy and safety of alisertib in patients with small cell neuroendocrine prostate cancer or metastatic prostate cancer plus at least one of the following: more than 50% neuroendocrine marker as determined by immunohistochemistry; new liver metastases without PSA progression; and more than five times serum chromogranin or more than two times serum neuron-specific enolase.
Study participants received 50 mg alisertib twice daily on days 1 through 7 every 21 days.
Six-month radiographic PFS served as the primary endpoint. Researchers determined a 6-month PFS rate of 15% or less as unacceptable, and a 6-month PFS rate of more than 30% as worthy of exploration.
Secondary outcomes included OS, radiographic response rate, PSA response rate and serum neuroendocrine markers in response to therapy.
Exploratory outcomes included the associations between circulating tumor DNA and tumor molecular features with clinical features and response.
The analysis included 60 patients (median age, 67 years; range, 45-87) who met pathologic or clinical criteria. Patients had a median PSA of 1.07 ng/mL (range, 0.01-514.2) and had undergone a median three prior therapies. Thirty-two percent of patients had received docetaxel, 58% had received platinum therapy, and 35% had received enzalutamide (Xtandi; Astellas, Medivation) or abiraterone acetate (Zytiga, Janssen).
More than half (54%) of patients had Gleason grade 8 to grade 10 disease. The most common metastatic sites were the bones (78%), lymph nodes (75%), liver (61%) and lungs (37%).
Fifty-seven patients discontinued treatment. The majority (n = 49; 86%) did so due to disease progression. Six (10%) discontinued due to adverse events, one discontinued at patient request and one discontinued due to an unrelated medical condition.
Median PFS was 8.7 weeks (range, 8-10.4). Six-month PFS rates were 12.6% overall and 15.2% for those with pathologically defined neuroendocrine prostate cancer.
Median OS was 9.5 months (95% CI, 7.3-13). Researchers reported no difference in OS between patients with neuroendocrine prostate cancer and those with adenocarcinoma.
Twenty-three patients (38%) experienced grade 3 or grade 4 toxicities, the most common of which were neutropenia (13%), gastrointestinal side effects (8%), fatigue (8%), and febrile neutropenia, anemia and elevated bilirubin (6.6% each).
Among 17 patients whose scans at cycle 3 showed stable disease, partial response or complete response, median PFS was 20 weeks (range, 17-121) and 6-month PFS was 35.8% (95% CI, 18.1-70.9).
Two patients achieved exceptional response, including complete resolution of liver metastases. A third patient demonstrated stable disease at 39 months follow-up.
Incorporation of metastatic biopsies across centers, whole-exome RNA sequencing and organoid development is feasible and may improve patient selection for alisertib treatment, Beltran said.
“Based on emerging preclinical data, as well as results from this trial, further investigation of targeting [Aurora kinase A] and the [Aurora kinase A–N-myc] therapeutic complex for neuroendocrine prostate cancer is warranted, but I do think biomarker selection will be critical for the design of any future trials in this area,” Beltran said. – by Mark Leiser
For more information: Beltran H, et al. Abstract LBA29. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Beltran reports research funding from Takeda/Millennium. The other researchers report no relevant financial disclosures.