2021 GU Cancers Symposium: Apalutamide Combo Boosts PFS in ACIS Trial of mCRPC

By Jennifer Lubell

Combining apalutamide (APA) with abiraterone acetate plus prednisone (AAP) reduced the risk of radiographic progression or death by 31% in patients with advanced prostate cancer who had never received chemotherapy, according to findings presented at the American Society of Clinical Oncology’s 2021 Genitourinary Cancers Symposium.

This combination yielded stronger outcomes than AAP alone, especially in certain patient subgroups, said Dana E. Rathkopf, MD, who presented the final results of ACIS, a randomized, double-blind, phase 3 study (Abstract 9) of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).

Activated androgen receptors and elevated intratumoral androgens frequently drive mCRPC and patients may need dual inhibition therapies. The prostate cancer therapies APA and abiraterone acetate possess distinct receptor inhibition and ligand suppression actions, respectively. “The purpose of the study was to assess whether a combination of these therapies plus prednisone would provide a better clinical benefit than AAP alone,” said Dr. Rathkopf, a medical oncologist at Memorial Sloan Kettering Cancer Center and the study’s principal investigator.

Investigators designated radiographic progression-free survival (rPFS) as the primary endpoint. Secondary/other endpoints included prostate-specific antigen (PSA) response, overall survival, safety, time to PSA progression, chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression.

Dr. Rathkopf and her colleagues compared rPFS in 982 chemotherapy-naive patients with mCRPC undergoing androgen deprivation therapy, randomizing them 1-to-1 to receive either APA and AAP, or AAP and placebo. Across both arms, approximately 10% of patients had lung metastases, and 4% had liver metastases. Each arm had incidence of bone, lymph node, and soft tissue disease.

Dana Rathkopf, MD

Patients were randomized for treatment from December 2014 to August 2016. Clinical cutoffs for the primary and final analyses took place in March 2018 and September 2020, respectively. Patients remained on study treatment until disease progression, withdrawal of consent, or unacceptable toxicity.

In the primary analysis, ACIS met its primary endpoint of rPFS by investigative review. After a median follow up of 25.7 months, the combination of APA plus AAP led to a 31% reduction in risk of radiographic progression or death, compared with AAP plus placebo.  The AAP plus APA combination extended median rPFS by approximately 6 months, compared with AAP (22.6 months vs. 16.6 months; Hazard Ratio [HR], 0.69; 95% CI: 0.58-0.83; P < 0.0001).

At the updated final analysis in September 2020, investigators reported that APA plus AAP extended rPFS by 7.4 months, with a consistent 30% reduction in radiographic progression or death.

Notably, subgroups of patients 75 years or older and patients with visceral metastasis both favored the combination treatment versus AAP alone. Patients with specific biomarker signatures may also derive enhanced benefit from the combination treatment, Dr. Rathkopf said. “Future studies will be needed to confirm these observations,” she said.

Compared with AAP and placebo, the APA plus AAP combination showed a significantly higher rate of confirmed ≥ 50% PSA decline. “However, this PSA decline favoring the combination arm translated into only a marginal delay in time to PSA progression,” Dr. Rathkopf said.

The combination of APA plus AAP also yielded a longer median overall survival, although this was not statistically significant.

Investigators reported no significant differences in chronic opioid use, initiation of cytotoxic chemotherapy, and pain progression between the two groups. The treatments produced no new safety signals, as the safety profile was consistent with prior drug experience.

Patients in the APA plus AAP arm did experience slightly higher rates of grade 3-4 treatment-emergent adverse events (63.3%) than patients in the AAP group (56.2%). “Although the incidence of grade 3-4 cardiac events were higher in the combination arm, this did not translate into a greater number of deaths,” Dr. Rathkopf said. “Patient quality of life was comparable between treatments.”

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