In the phase 3 ACIS study, the addition of apalutamide to abiraterone acetate lead to a reduction in the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer receiving androgen deprivation therapy.
In the phase 3 ACIS study, the addition of apalutamide (Erleada) to abiraterone acetate (Zytiga) lead to a reduction in the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) receiving androgen deprivation therapy (ADT), according to the final analysis data presented during the 2021 Genitourinary Cancers Symposium.1
The final results showed that at a median follow-up of 54.8 months, the median radiographic progression-free survival (rPFS) was 24 months with the addition of apalutamide compared with 16.6 months with placebo plus abiraterone and prednisone (HR, 0.70). The data sustained the rPFS benefit with apalutamide observed at the primary efficacy analysis conducted at a median follow-up of 25.7 months: 22.6 months with apalutamide versus 16.6 months in the control arm (HR, 0.69; P <.0001).
The rPFS benefit with apalutamide/abiraterone was sustained across prespecified subgroups. “Notably, the subgroups of patients aged 75 years or older and patients with visceral metastasis both favored the combination versus abiraterone/prednisone alone,” said principal investigator Dana Rathkopf, MD, medical oncologist, Memorial Sloan Kettering Cancer Center.
Although the study met its primary end point with a statistically significant rPFS benefit in the apalutamide arm, analyses of secondary end points showed no significant difference in outcomes between the study arms with secondary outcome measures, including overall survival (OS), time to initiation of cytotoxic chemotherapy, pain progression, and chronic opioid use.
The double-blind phase 3 ACIS study included 982 patients with chemotherapy-naïve mCRPC who received ADT. Baseline characteristics were well balanced between the 2 treatment arms. Overall, the median patient age was 71 years, about 53% of patients had a Gleason score greater than 7, the median prostate-specific antigen (PSA) level was about 32 ng/mL, and all patients had an ECOG performance status of 0 (68%) or 1 (32%).
“Approximately 10% of patients had lung metastases and 4% had liver metastases in both arms. Bone, lymph node, and soft tissue disease were equally distributed, as well,” said Rathkopf.
Patients were randomized 1:1 to apalutamide (n = 492) or placebo (n = 490) plus abiraterone and prednisone. All patients remained on continuous ADT. Patient randomization occurred between December 10, 2014, and August 30, 2016.
At the final analysis, 79.5% of patients in the apalutamide/abiraterone arm had a PSA decline of 50% or greater compared with 72.9% in the control arm (P = .015). Also, 24.6% versus 19.2% of the 2 arms, respectively, had undetectable PSA (<0.2 ng/mL) at any time during treatment (P = .040). However, the improved PSA decline with the apalutamide/abiraterone combo did not translate into a significant benefit in median time to PSA progression at 13.8 months versus 12 months in the control arm (P = .076).
The median OS was 36.2 months with apalutamide/abiraterone versus 33.7 months in the control arm (P = .498). The time to initiation of cytotoxic chemotherapy was 36.1 months versus 34.2 months, respectively (P = .509). The times to chronic opioid use and pain progression were 47 months versus 53.3 months (P = .500) and 21.8 months versus 26.5 months (P = .188), respectively.
“After discontinuing treatment on the ACIS trial, two-thirds of patients [across the trial] received subsequent life-prolonging therapies,” said Rathkopf. Among these treatments, docetaxel was received by about 70% of patients and enzalutamide (Xtandi) was received by about 20% of patients.
Regarding toxicity, no new safety signals were reported compared with previous reported studies of apalutamide. About two-thirds (63.3%) of patients in the apalutamide arm experienced treatment-emergent adverse events (TEAEs), compared with 56.2% of patients in the control group.
Several grade 3/4 TEAEs were more common in the apalutamide/abiraterone combination arm compared with the control arm: hypertension (20.6% vs 12.5%), fatigue (4.7% vs 3.9%), cardiac disorders (9% vs 5.7%), fall (3.3% vs 0.6%), skin rash (4.5 percent vs. 0.4 percent), seizures (0.2% vs 0), and fractures and osteoporosis (4.1% vs 1.4%).
Also of note, as measured by the Functional Assessment of Cancer Therapy–Prostate (FACT-P Total), quality of life was comparable between the apalutamide/abiraterone and control arms.
In her concluding remarks, Rathkopf noted that there was a trend toward better OS outcomes with the apalutamide/abiraterone combination in certain prespecified biomarker subgroups, such as luminal histology or high androgen activity.
“Future studies will be need to confirm these observations,” said Rathkopf.
The androgen receptor inhibitor apalutamide is currently approved by the FDA for the treatment of patients with nonmetastatic CRPC. The CYP17 inhibitor abiraterone has FDA-approved indications for use in combination with prednisone in patients with metastatic CRPC and metastatic high-risk castration-sensitive prostate cancer.
Rathkopf DE, Efstathiou E, Attard G, et al. Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 Genitourinary Cancers Symposium. February 11-13, virtual. Accessed February 11, 2021. http://bit.ly/3tPysjZ