Apalutamide Added to SOC Improves Survival in Men With mCRPC

Apalutamide (Erleada) plus abiraterone/prednisone improved radiographic progression-free survival (PFS) in patients with metastatic, castration-resistant prostate cancer (mCRPC), according to results from a phase 3 trial published in The Lancet Oncology.

mCRPC is a uniformly fatal disease, and the majority of patients affected will develop disease progression. While mCRPC is driven by both activated androgen receptors and elevated intratumoral androgens, the current standard of care therapy only targets a single androgen signaling mechanism. Combination treatment may improve response, according to prior research.

The phase 3 ACIS trial was designed to compare the efficacy of apalutamide in combination with abiraterone acetate/prednisone versus abiraterone acetate/prednisone alone. It has an actual enrollment of 982 participants and a primary end point of radiographic PFS. Secondary end points include overall survival, time to chronic opioid use, time to the initiation of cytotoxic chemotherapy, and time to pain progression.

Patients were randomized 1:1 into a control and experimental arm. In the experimental arm, patients received apalutamide 240 mg and abiraterone acetate 1000 mg once daily on an empty stomach and 5 mg of prednisone twice daily, until disease progression, unacceptable toxicity, or end of treatment. In the control arm, patients received the same regimen with the exception of a placebo in place of apalutamide.

In the experimental arm (n = 492), the median age was 71 (range, 66-78), 74% where White, 86% were not Hispanic or Latino, Gleason score at initial diagnosis include < 7 (10%), 7 (33%), and > 7 (53%). Sixty-nine percent had an ECOG score of 0. Previous prostate cancer therapies included prostatectomy (26%), radiotherapy (54%), hormonal (1005), adjuvant or neoadjuvant chemotherapy (2%), and other (14%).

Thirty-two percent of patients received a previous bone protective agent, and the rate of the presence of visceral metastasis at randomization was 15%. Site of disease at baseline include bone (83%), bone only (42%), lymph node (48%), soft tissue (12%), adrenal gland (1%), liver (4%), and lung (11%). Evidence of disease progression at baseline included prostate-specific antigen (88%), radiographic bone (34%), and radiographic soft tissue or lymph node (26%). Tumor stage at diagnosis includes T0-2 (29%), T3-4 (50%), and unknown (21%). Forty-six percent of patients had a lymph node stage of N0 at diagnosis and 47% had a metastasis stage at diagnosis of M0. Sixty-nine percent of patients had ≤ 10 bone lesions at baseline. Additionally, 68% reported their worst pain in the past 24 hours being 0-1. The median prostate-specific antigen receptor at baseline is 32.3 ng/mL (range, 11.5-91.4). The median alkaline phosphatase at baseline was 92 IU/L (range, 69-139). Median lactate dehydrogenase at baseline was 186 IU/L (range, 167-215).

In the control arm (n = 490), the median age was 71 (range, 65-77), and 76% were white. Eighty-four percent were not Hispanic or Latino. Gleason scores at initial diagnosis included <7 (9%), 7 (33%), and >7 (53%). Over half of patients, 68%, had an ECOG score of 0 at baseline. Previous prostate cancer therapies included prostatectomy (30%), radiotherapy (49%), hormonal (100%), adjuvant or neoadjuvant chemotherapy (2%), and other (16%).

A previous bone protective agent was given to 31% of patients and the rate of presence of visceral metastasis at randomization was 14%. Sites of disease at baseline included bone (87%), bone only (42%), lymph node (47%), soft tissue (14%), adrenal gland (1%), liver (4%), and lung (10%). Evidence of disease progression at baseline included prostate-specific antigen (90%), radiographic bone (36%), radiographic soft tissue of lymph node progression (26%). Tumor stage at diagnosis included T0-2 (26%), T3-4 (53%), and unknown (22%).

Lymph node stage at diagnosis included N0 (43%), N1 (24%), and unknown (33%). Metastasis stage at diagnosis included M0 (42%), M1 (35%), and unknown (23%). Sixty-six percent of patients at ≤10 at baseline and 64% reported worst pain during the past 24 hours between 0 and 1. The median prostate-specific antigen receptor at baseline is 31.2 ng/mL (range, 12.2-106.5). The median alkaline phosphatase at baseline was 91 IU/L (range, 68-138). Median lactate dehydrogenase at baseline was 188 IU/L (range, 167-221).

The median OS was 36.2 months (range, 32.8-38.8) in the experimental arm and 33.7 months (range, 31.2-38.3) in the control arm. In the experimental arm, the median time to the initiation of cytotoxic chemotherapy was 36.1 months (range, 32.2-42.6) compared to 34.2 months (range, 29.5-39.2) in the control arm (HR 0.94, 95% CI,0.78-1.13, P = .51). The time to chronic opioid use was 47 months (range, 39.2-NE) in the experimental arm and 53.3 months (range, 42-NE) in the control arm (HR 1.07, 95% CI, 0.87-1.32, P = 50). In the experimental arm, the time to pain progression was 21.8 months (range, 18-25.7) compared with 26.5 months (range, 22.6-29.5) in the control arm (HR 1.12, 95% CI, 0.95-1.33, P = 0.19). The objective response rate (ORR) was 38% at baseline, with 58% being responders in the experimental arm. In the control arm, the ORR was 33% with 53% being responders.

The median time to clinical progression was 16 months (range, 14.3-17.3) in the experimental arm and 18.1 months (range, 16.4-19.8) in the control arm (HR, 1.10; 95% CI, 0.96-1.27; P = 0.18). The time to second PFS was 31.8 months (range, 28.4-36.9) in the experimental arm and 30.2 months in the control arm (HR, 0.92; 95% CI, 0.78-1.08; P = 0.31).

Grade 3/4 adverse events (AEs) occurred at a rate of 60% in the experimental arm and 51% in the control arm. AEs led to death in 3% of patients in the experimental arm and 8% in the control arm. Treatment-related AEs in led to discontinuation in 9% of patients in the experimental arm and 6% in the control arm. 

“Despite the comparison with an active therapy and use as first-line treatment, apalutamide plus abiraterone/prednisone consistently improved radiographic progression-free survival in chemotherapy-naive mCRPC patients versus abiraterone/prednisone, while maintaining quality of life,” wrote study authors.

_REFERENCE:

_{Saad F, Efstathiou E, Attard G, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021;22(11):1541-1559. doi: 10.1016/ S1470-2045(21)00402-2}