Non-Metastatic Castration Resistant Prostate Cancer

ARAMIS (NCT02200614) was a multicenter, double-blind, placebo-controlled clinical trial in 1509 patients with non-metastatic castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months. Randomization was stratified by PSADT and use of bone-targeted therapy at study entry. Patients with pelvic lymph nodes less than 2 cm in short axis below the aortic bifurcation and patients with a history of seizures were eligible to enter the study. Absence or presence of metastasis was assessed by blinded independent central review (BICR). PSA results were not blinded and were not used for treatment discontinuation. 

Patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). Treatment continued until radiographic disease progression as assessed by CT, MRI, 99mTc bone scan by BICR, unacceptable toxicity or withdrawal. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy. 

The following patient demographics and disease characteristics were balanced between treatment arms. The median age was 74 years (range 48–95) and 9% of patients were 85 years of age or older. The racial distribution included 79% White, 13% Asian, 3% Black or African American, while ethnicity included 3.1% Hispanic or Latino patients. A majority of patients (73%) had a Gleason score of 7 or higher at diagnosis. The median PSADT was 4.5 months. Forty-two percent of patients in both treatment arms had prior surgery or radiotherapy to the prostate. Eleven percent of patients had enlarged pelvic lymph nodes less than 2 cm at study entry. Six percent of patients were retrospectively identified by BICR as having metastases at baseline. Seventy-three percent of patients received prior treatment with an anti-androgen (bicalutamide or flutamide). All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry. There were 12 patients enrolled on the NUBEQA arm with a history of seizure. At baseline, 47% of patients reported no pain on the Brief Pain Inventory-Short Form (a 7-day diary average of the daily worst pain item).

The major efficacy endpoint was metastasis free survival (MFS), defined as the time from randomization to the time of first evidence of BICR-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above the aortic bifurcation. Overall survival (OS), time to pain progression, and time to initiation of cytotoxic chemotherapy, were additional efficacy endpoints. 

Treatment with NUBEQA resulted in a statistically significant improvement in MFS compared to placebo. At the protocol-specified final analysis of OS, treatment with NUBEQA resulted in a statistically significant improvement in OS compared to placebo. The final analysis of OS and time to initiation of cytotoxic chemotherapy was event-driven and conducted after 254 OS events had occurred. The efficacy results from ARAMIS are summarized in Table 5 and Figure 1.

Figure 1: Kaplan-Meier Curve Metastasis Free Survival; Intent-To-Treat nmCRPC population (ARAMIS) 

Figure 2: Kaplan-Meier curves of Overall Survival; Intent-To-Treat nmCRPC population (ARAMIS)

MFS results were consistent across patient subgroups for PSADT (≤ 6 months or > 6 months) or prior use of bone-targeting agents (yes or no). 

Treatment with NUBEQA resulted in a statistically significant delay in time to pain progression (HR = 0.65, 95% CI= 0.53, 0.79; p < 0.0001). Time to pain progression was defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory Short Form or initiation of opioids and reported in 28% of all patients on study.

Treatment with NUBEQA resulted in a statistically significant delay in the initiation of cytotoxic chemotherapy (HR = 0.58, 95% CI = 0.44, 0.76; p < 0.0001).

Metastatic Hormone-Sensitive Prostate Cancer

ARASENS (NCT02799602) was a multicenter, double-blind, placebo-controlled clinical trial in 1306 patients with mHSPC. Patients were randomized 1:1 to receive 600 mg darolutamide orally twice daily (n=651) or matching placebo (n=655), concomitantly with 75 mg/m2 of docetaxel for 6 cycles. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a bilateral orchiectomy. Treatment with NUBEQA or placebo continued until symptomatic progressive disease, change of antineoplastic therapy, or unacceptable toxicity. Patients with regional lymph node involvement only (M0) were excluded from the study. Patients were stratified by extent of disease (non–regional lymph nodes metastases only (M1a), bone metastases with or without lymph node metastases (M1b) or visceral metastases with or without lymph node metastases or with or without bone metastases (M1c)) and by alkaline phosphatase level (< or ≥ upper limit of normal) at study entry. 

The following patient demographics and disease characteristics were balanced between treatment arms. The median age was 67 years (range 41–89) and 17% of patients were 75 years of age or older. The racial distribution included 52% White, 36% Asian, 4% Black, while ethnicity included 7% Hispanic patients. Seventy-eight percent (78%) of patients had a Gleason score of ≥8 at diagnosis. Seventy one percent (71%) of patients had an ECOG performance status score of 0 and 29% patients had an ECOG performance status score of 1. There were 86% of patients with de novo and 13% with recurrent disease. At initial diagnosis of metastatic disease, 3% had M1a, 83% had M1b and 14% had M1c disease; alkaline phosphatase was < ULN in 45% of patients and ≥ ULN in 55% of patients; median PSA level at baseline was 30 µg/L and 24 µg/L for NUBEQA vs placebo group, respectively. Patients with a medical history of seizure were allowed to enter the study, and 4 patients (0.6%) were enrolled in the NUBEQA with docetaxel arm.

The major efficacy outcome measure was overall survival (OS). Time to pain progression was an additional efficacy outcome measure. 

Treatment with NUBEQA with docetaxel resulted in a statistically significant improvement in OS compared to placebo with docetaxel. OS results were consistent across stratified subgroups (extent of disease and alkaline phosphatase level).

    NR: not reached

Figure 3: Kaplan-Meier curves of Overall Survival; mHSPC population (ARASENS)

Treatment with NUBEQA with docetaxel resulted in a statistically significant delay in time to pain progression (HR = 0.79, 95% CI= 0.66, 0.95; 1-sided p value = 0.006). Time to pain progression was defined as the time from randomization to the time of pain progression. Pain progression is defined as: 

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    An increase of 2 or more points in the “worst pain in 24 hours” score (WPS) from nadir observed at 2 consecutive evaluations at least 4 weeks apart, or initiation of short- or long-acting opioid use for pain for at least 7 consecutive days, for asymptomatic patients (WPS=0) at baseline
•
    An increase of 2 or more points in the “worst pain in 24 hours” score (WPS) from nadir observed at 2 consecutive evaluations at least 4 weeks apart, and a WPS of 4 or greater, or initiation of short- or long-acting opioid use for pain for at least 7 consecutive days, for symptomatic patients (WPS ≥ 1) at baseline

Patients with opioid use within 4 weeks before randomization were censored at randomization in this analysis (125 patients (19%) in the NUBEQA with docetaxel arm and 118 patients (18%) in the placebo with docetaxel arm).