Androgen Annihilation Strategy Prolongs rPFS in mCRPC

Susan London

February 12, 2021

An androgen annihilation strategy using apalutamide significantly slows progression in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), according to final results from the phase 3 ACIS trial.

Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial's primary analysis and by 7.4 months at the trial's final analysis. Adverse events were consistent with the drug's known safety profile.

These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).

"mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens," said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.

Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.

With this in mind, investigators conducted the ACIS trial, enrolling 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.

Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.

Study Outcomes

The trial met its primary endpoint, Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).

Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.

For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.

The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).

Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.

Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.

"Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC," Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.

"It's not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on," she elaborated. "And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination."

Practice Changing?

To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.

However, "because of the increase in toxicity, cost, similar radiographic progression-free survival two, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time," he said.

Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Alumkal maintained.

"To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment," he elaborated. "Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS."

The ACIS study was funded by Janssen Research and Development. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....