Enzalutamide + Abiraterone Acetate in Bone CRPC

[pjoshea13]

New study below [1].

Abiraterone [Zytiga, Abi] & Enzalutamide [Xtandi, Enza] both target the androgen receptor [AR] axis, with Abi limiting the supply of androgens & Enza restricting access to the AR itself. It might seem worthwhile to combine the two, but that would depend on how effective the drugs are.

In the new (to PubMed) study:

"Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC."

"This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer."

The men had already failed basic ADT. It would be interesting to know the effect of Abi+Enza as an alternative to basic ADT, i.e. in men who have never received basic ADT (& are therefore not castrate resistant.)

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/314...

Eur Urol Oncol. 2019 Apr 19. pii: S2588-9311(19)30009-4. doi: 10.1016/j.euo.2019.01.008. [Epub ahead of print]

Enzalutamide in Combination with Abiraterone Acetate in Bone Metastatic Castration-resistant Prostate Cancer Patients.

Efstathiou E1, Titus M2, Wen S3, Troncoso P4, Hoang A2, Corn P2, Prokhorova I4, Araujo J5, Dmuchowski C6, Melhem-Bertrandt A6, Patil S6, Logothetis CJ2.

Author information

1

Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA; Department of Clinical Therapeutics, University of Athens, Athens, Greece. Electronic address: [e-mail].

2

Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.

3

Department of Biostatistics, West Virginia University, Morgantown, WV, USA.

4

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

5

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

6

Astellas Pharma, Inc., Northbrook, IL, USA.

Abstract

BACKGROUND:

It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone.

OBJECTIVE:

To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).

DESIGN, SETTING, AND PARTICIPANTS:

This open-label, single-centre interventional study was conducted in bmCRPC patients.

INTERVENTION:

Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated.

RESULTS AND LIMITATIONS:

Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ∼23% lower (range 14.05-200.5ng/ml) than when given alone.

CONCLUSIONS:

Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC.

PATIENT SUMMARY:

This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Abiraterone acetate; Bone metastases; Castration-resistant prostate cancer; Enzalutamide; Safety; Tolerability

PMID: 31412017 DOI: 10.1016/j.euo.2019.01.008

[cesces]

Am I missing something here, or is this a single arm study with no control group?

[6357axbz]

Thanks Patrick

[snoraste]

The last sentence in the conclusion seems to be saying the opposite. Am I misreading it?

[pjoshea13 in reply to snoraste]

Says that it is safe, but if there is no significant benefit ...

-Patrick