In chemotherapy-naïve patients, median OS was not reached for men with normal AR gene and was 12.40 months for AR gain. With a hazard ratio (HR) of 3.98, men with AR gain had about a 4 times greater higher risk of death compared with men with normal AR gene (< .001).

Among men who received prior docetaxel therapy, median OS was 21.80 months for patients with normal AR gene and 9.51 months for those with AR gain (HR: 3.81; < .001).


Continue Reading

PFS results were similar: chemotherapy-naïve men with AR gain had about a 2.2 times higher risk for disease progression (HR: 2.18; = .03); men previously treated with docetaxel had about a 2.0 times higher risk for disease progression (HR: 1.95; = .01). 

For AR gene mutations (2105T>A; 2632A>G) in abiraterone-treated, post-docetaxel patients, median OS was not reached in men with normal AR gene and was 4.06 months in men with AR gene mutations (HR: 3.06; = .004).

In a multivariate analysis, AR gain or mutations remained significantly associated with worse OS and PFS. 

A prostate-specific antigen (PSA) decline of greater than 50% was 4 to 5 times less likely among patients with AR gain and mutations. 

These findings were confirmed in the second cohort of 94 patients from the PREMIERE Study. Men with AR gain had an 8-fold higher risk for disease progression. 

RELATED: ASCO Releases Opinion on Hormonal Therapy for Castrate-resistant Prostate Cancer

Currently, there is no approved test for individualizing therapy for patients. But Dr D’Amico indicated that, in future, liquid biopsies may be able to identify men who may be appropriate for treatment with enzalutamide and abiraterone based on AR gene status.  As example, he noted that men who are deemed resistant to abiraterone or enzalutamide based on AR-V7 are often sensitive to docetaxel. 

The test will next be validated in prospective, clinical trials.

References

  1. Conteduca A, Wetterskog D, Sharabani MT, et al. Androgen receptor gene status in plasma DNS associates with worse outcome on enzalutamide or abiraterone for castrate-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Oncol. 2017 May 3. doi: 10.1093/annonc/mdx155 [Epub ahead of print] 
  2. Romanel A, Gasi Tandefelt D, Conteduca V, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;315:312re10.
  3. Salvi S, Casadio V, Conteduca V, et al. Circulating cell-free AR and CYP17A1 copy number variants may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone. Br J Cancer. 2015;112;1717-24.
  4. Salvi S, Casadio V, Conteduca V, et al. Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget. 2016;7:37839-45.
  5. Wyatt AW, Azad AA, Volik SV, et al. Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1598-606. 
  6. Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1(5):582-91.