Zytiga and Prednisone Plus Erleada Reduces Risk of Disease Progression in Prostate Cancer Subtype

Treatment with Zytiga (abiraterone acetate), Erleada (apalutamide) and the steroid prednisone reduced the risk of radiographic progression or death by 30% in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) receiving androgen deprivation therapy.

Final data from the phase 3 ACIS study, which were presented during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium, showed that at a median follow-up of 54.8 months, the median radiographic progression-free survival (an endpoint that determines treatment benefit) was 24 months with the addition of Erleada compared to 16.6 months with placebo plus Zytiga and prednisone.

The radiographic progression-free survival benefit with the Zytiga and Erleada combination was sustained across certain patient subgroups. “Notably, the subgroups of patients aged 75 years or older and patients with visceral metastasis both favored the combination versus (Zytiga/prednisone) alone,” said lead study author Dr. Dana Rathkopf, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, in a presentation of the data.

Although the study’s main goal of a radiographic progression-free survival benefit in the Erleada treatment arm was reached, analyses of other goals showed no significant difference in outcomes 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 (median age, 71 years) with chemotherapy-naive metastatic castration-resistant prostate cancer who received androgen deprivation therapy. Baseline characteristics were well balanced between the two treatment arms.

“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 to receive either Erleada (492 patients) or placebo (490 patients) plus Zytiga and prednisone. All patients remained on continuous androgen deprivation therapy.

At the final analysis, 79.5% of patients in the Erleada/Zytiga arm had a prostate-specific antigen (PSA) decline of 50% or greater compared with 72.9% in the control arm. Also, 24.6% versus 19.2% of the two arms, respectively, had undetectable PSA levels at any time during treatment.

However, the improved PSA decline with the Erleada and Zytiga combination did not translate into a significant benefit in median time to PSA progression at 13.8 months versus 12 months in the control arm.

PSA, according to the Mayo Clinic, is a protein that is produced by cancerous and noncancerous tissue in the prostate and increased levels may indicate cancer.

Patients in the Erleada and Zytiga treatment arm achieved a median overall survival of 36.2 months compared to 33.7 months in the control arm. The time to initiation of cytotoxic chemotherapy was 36.1 months versus 34.2 months, respectively. The times to chronic opioid use and pain progression were 47 months versus 53.3 months and 21.8 months versus 26.5 months, 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, the chemotherapy docetaxel was administered to approximately 70% of patients and Xtandi (enzalutamide) was received by about 20% of patients.

Patients didn’t report any new side effects and the toxicity data were similar to what has been previously reported with Erleada. About two-thirds (63.3%) of patients in the Erleada arm experienced treatment-emergent adverse events, compared to 56.2% of patients in the control group.

Several grade 3 and 4 (more serious and severe) treatment-emergent adverse events were more common in the Zytiga and Erleada combination arm compared to 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%).

Rathkopf noted that there was a trend toward better overall survival outcomes with the Zytiga and Erleada combination in certain prespecified biomarker subgroups, such as patients with luminal histology or high androgen activity.

“Future studies will be need to confirm these observations,” she concluded.

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