Androgen-Annihilation Therapy Prolongs Progression-Free Survival in Metastatic Prostate Cancer

By Reuters Staff

October 25, 2021

NEW YORK (Reuters Health) - Among men with metastatic castration-resistant prostate cancer (mCRPC), androgen-annihilation therapy significantly improved radiographic progression-free survival (rPFS) in the ACIS trial.

Androgen-annihilation therapy involves dual inhibition of the androgen-signaling pathway using therapies that suppress androgen signaling in different ways. This is accomplished by combining apalutamide with abiraterone-prednisone.

The ACIS trial was a randomized, phase-3, placebo-controlled study testing this strategy in 982 men with mCRPC. All were receiving ongoing androgen-deprivation therapy but none had previously received chemotherapy or androgen-biosynthesis-signaling inhibitors.

Patients were randomly allocated to oral apalutamide (240 mg once daily) plus oral abiraterone acetate (1,000 mg once daily) and oral prednisone (5 mg twice daily) or placebo plus abiraterone acetate and prednisone, in 28-day treatment cycles.

After median follow-up of 25.7 months, median rPFS was 22.6 months with apalutamide versus 16.6 months without (hazard ratio, 0.69; 95% confidence interval, 0.58 to 0.83).

At the final analysis with around 4.5 years of follow-up, the significant rPFS survival benefit with apalutamide was maintained (median rPFS: 24.0 months vs. 16.6 months; HR, 0.70; 95% CI, 0.60 to 0.83).

There were no significant between-group differences in the secondary endpoints of overall survival, time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to pain progression.

"Safety was consistent with the previously reported safety profile of the individual drugs and patient-reported health-related quality of life was maintained," Dr. Fred Saad with University of Montreal in Canada and colleagues report in The Lancet Oncology.

"The ACIS study highlighted potential long-term clinical benefits associated with the combination of apalutamide and abiraterone-prednisone," they write. "Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC."

The co-authors of a linked comment say while the ACIS study results are "unlikely to change clinical practice, several important lessons could be learned to guide future drug development."

There continues to be a "huge unmet need for drugs with novel mechanisms of action backed by strong preclinical and clinical rationales in this setting," write Dr. Umang Swami and Dr. Neeraj Agarwal of Huntsman Cancer Institute at the University of Utah, in Salt Lake City.

"Despite setbacks with combination regimens in mCRPC, multiple novel regimens based on strong preclinical rationale and promising early clinical data are in advanced phases of development. These regimens include various PARP inhibitors combined with androgen receptor signaling inhibitors (abiraterone or enzalutamide) in patients selected for underlying homologous recombinant repair mutations and unselected patients with mCRPC, and selected patients with metastatic castration-sensitive prostate cancer."

"On the basis of these exciting advances, the development of novel therapeutic agents or combinations for patients with mCRPC has great potential," they say.

Funding for the study was provided by Janssen Research and Development. Several authors have financial relationships with the company.

SOURCE: https://bit.ly/2WUDvnM and https://bit.ly/3iFJULk The Lancet Oncology, online September 30, 2021.

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