Orteronel Plus ADT Misses OS End Point in Metastatic Hormone-Sensitive Prostate Cancer

Neeraj Agarwal, MD

The addition of orteronel (TAK-700) to androgen deprivation therapy (ADT) vs bicalutamide improved progression-free survival (PFS) and prostate-specific antigen (PSA) response in patients with metastatic hormone-sensitive prostate cancer (mHSPC), but missed the primary end point of overall survival (OS) in the phase 2 SWOG-1216 trial (NCT01809691).¹

Results, which were published in the Journal of Clinical Oncology, showed that at a median follow-up of 4.9 years, the median OS with orteronel/ADT was 81.1 months vs 70.2 months with bicalutamide/ADT. The 5-year OS rates in the investigative and control arms were 59.7% and 57.9%, respectively (HR, 0.86; 95% CI, 0.72-1.02; P = .040), which did not cross the boundary for statistical significance.

The median PFS with orteronel/ADT was 47.6 months vs 23.0 months with bicalutamide/ADT. The 4-year PFS rate in the investigative arm was 50.2% vs 33.9% in the control arm (HR, 0.58; 95% CI, 0.51-0.67; P < .001). Moreover, the PSA response rate at month 7 was significantly improved with the addition of orteronel to ADT vs bicalutamide (P < .0001).

“These results indicate that orteronel is likely not an effective androgen axis inhibitor compared with recently approved agents in this setting,” lead study author Neeraj Agarwal, MD, of the University of Utah Huntsman Cancer Institute, and colleagues, wrote in the paper. “Higher than anticipated OS of patients in the control arm is reflective of therapeutic advancements made over the past decade in men with metastatic prostate cancer.”

ADT, along with medical or surgical castration, continues to be staple in the treatment of patients with metastatic HSPC; however, patients ultimately experience disease progression. Intensification of ADT docetaxel or abiraterone acetate (Zytiga) has resulted in improved survival, and agents such as apalutamide (Erleada) and enzalutamide (Xtandi) have entered the paradigm and improved outcomes, but these approaches are not without challenges.

Orteronel has been shown to inhibit CYP17, 20 lyase with stronger specificity vs CYP17 hydroxylase compared with abiraterone acetate. Notably, orteronel has not been found to result in the syndrome of secondary mineralocorticoid excess.

The open-label, multicenter S1216 trial enrolled patients with histologically confirmed adenocarcinoma of the prostate and metastatic disease who had a Zubrod performance status of 0 to 2 and could not have previously received systemic therapy for metastatic disease. Moreover, at least 6 months must have passed since previous neoadjuvant and/or adjuvant ADT had been completed.

The trial permitted patients who had not started treatment with a LHRH agonist, antagonist, or orchiectomy, and those who had already initiated a LHRH agonist, antagonist, or orchiectomy within 30 days before registration to the trial.

Patients could not have brain metastases, and they could not have previously received ketoconazole, abiraterone acetate, or enzalutamide. Other exclusion criteria included having New York Heart Association class III or IV heart failure at screening or a thromboembolic event, unstable angina pectoris, myocardial infarction, or serious uncontrolled cardiac arrhythmia within 6 months prior to registration.

Study participants were randomized 1:1 to orteronel at a twice-daily dose of 300 mg (n = 638) or bicalutamide at a daily dose of 50 mg (n = 641) plus continuous ADT.

Key stratification factors included severity of disease (minimal vs extensive), Zubrod performance status (0 to 1 vs 2 to 3), and preregistration treatment status (early vs late induction).

The primary end point of the trial was OS, and secondary end points comprised PFS, PSA response rates, and safety.

The demographic and clinical characteristics of study participants were noted to be well balanced between the arms. The median age of patients in the investigative arm was 67.6 years vs 68.1 years in the control arm. Across the arms, approximately 10% of patients were African American, 49% had extensive disease, and 96% of patients had a Zubrod performance status ranging from 0 to 1.

More evaluable patients in the bicalutamide/ADT arm (n = 402) went on to receive post-protocol therapy vs those in the orteronel/ADT arm (n = 331). Specifically, 61.3% and 77.4% of those in the investigative and control arms, respectively, received at least 1 life-prolonging anticancer therapies.

Regarding safety, grade 3 or 4 adverse effects (AEs) occurred in 43% of patients who received orteronel vs 13% of those who were given bicalutamide. Higher rates of hypertension (20%) and fatigue (5%) were experienced in the investigative arm vs 5% and 2%, respectively, in the control arm. Grade 5 AEs were reported in 5 patients in the orteronel arm and 1 patient in the bicalutamide arm; 2 of these patients reported myocardial infarction and 1 had a stroke in the investigative arm.

Reference

Agarwal N, Tangen CM, Hussain MHA, et al. Orteronel for metastatic hormone-sensitive prostate cancer: a multicenter, randomized, open-label phase III trial (SWOG-1216). J Clin Oncol. Published online April 21, 2022. doi:10.1200/JCO.21.02517