Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, CRPC

[pjoshea13]

New study below [1].

"The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC."

"982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone).

"At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months ... in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69 ...).

"At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months... versus 16·6 months (13·9-19·3; HR 0·70 ...)."

"Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/346...

Lancet Oncol

. 2021 Sep 30;S1470-2045(21)00402-2. doi: 10.1016/S1470-2045(21)00402-2. Online ahead of print.

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

Fred Saad 1 , Eleni Efstathiou 2 , Gerhardt Attard 3 , Thomas W Flaig 4 , Fabio Franke 5 , Oscar B Goodman Jr 6 , Stéphane Oudard 7 , Thomas Steuber 8 , Hiroyoshi Suzuki 9 , Daphne Wu 10 , Kesav Yeruva 10 , Peter De Porre 11 , Sabine Brookman-May 12 , Susan Li 13 , Jinhui Li 14 , Shibu Thomas 13 , Katherine B Bevans 15 , Suneel D Mundle 16 , Sharon A McCarthy 16 , Dana E Rathkopf 17 , ACIS Investigators

Affiliations collapse

Affiliations

1 Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, QC, Canada. Electronic address: [e-mail].

2 Athens Medical Center, Dept of GU Oncology, Athens, Greece.

3 University College London, London, UK.

4 University of Colorado Cancer Center, Aurora, CO, USA.

5 ONCOSITE, Hospital Unimed Noroeste, Ijuí, Brazil.

6 Comprehensive Cancer Centers of Nevada, US Oncology Network, Las Vegas, NV, USA.

7 Georges Pompidou Hospital, University of Paris, Paris, France.

8 Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

9 Toho University Sakura Medical Center, Chiba, Japan.

10 Janssen Research & Development, Los Angeles, CA, USA.

11 Janssen Research & Development, Beerse, Belgium.

12 Janssen Research & Development, Los Angeles, CA, USA; Ludwig Maximilians University, Munich, Germany.

13 Janssen Research & Development, Spring House, PA, USA.

14 Janssen Research & Development, San Diego, CA, USA.

15 Janssen Global Services, Horsham, PA, USA.

16 Janssen Research & Development, Raritan, NJ, USA.

17 Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA.

PMID: 34600602 DOI: 10.1016/S1470-2045(21)00402-2

Abstract

Background: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.

Methods: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.

Findings: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).

Interpretation: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.

Funding: Janssen Research & Development.

Copyright © 2021 Elsevier Ltd. All rights reserved.

[cesces]

Was there not a prior study that came to the opposite conclusion?

[tango65 in reply to cesces]

There is a study combining enzalutamide and abiraterone that didi not show improving of OS

cancernetwork.com/view/more...

[tango65]

Same survival and more side effects.

[CAMPSOUPS in reply to tango65]

Do you mean with this Aptalutamide with Abiraterone combo or with the Enzi with Abi combo?(I.E. your comment same survival more side effects)

I recall the Enzi with Abi had quite severe side effects.

This Aptalutamide with Abi information I don't know what to do with.

As a "kitchen sink" rather than Abi alone?

Would it be good when Abi and subsequently Enzi fail or would resensitizing with Platinum chemo to try for another round of Abi or Enzi be best.

Shorter comment is I don't really know when this Aptalutamide/Abiraterone combo would best be considered for implementing.

[tango65 in reply to CAMPSOUPS]

It does not prolong survival and you will get more side effects if taking together. Perhaps taking one and when it fails having chemo which can re sensitize the cancer to anti androgens try other anti androgen.

[Grumpyswife]

Similarly, my husband started taking darolutamide with abiraterone on 9/14/2021. He is now at full dose daro and half dose abi with no prednisone yet. His PSA dropped from 168 to 73 in under a month. However, we were reminded that we are not treating for PSA.

He has blood work today to verify and has not yet seen worsening of side effects besides fatigue.

[CAMPSOUPS]

This Aptalutamide with Abi information I don't know what to do with.

As a "kitchen sink" rather than Abi alone?

Would it be good when Abi and subsequently Enzi fail or would resensitizing with Platinum chemo to try for another round of Abi or Enzi be best.

Shorter comment is I don't really know when this Aptalutamide/Abiraterone combo would best be considered for implementing.