Neoadjuvant therapy that combines abiraterone acetate plus prednisone (AAP) and leuprolide prior to radical prostatectomy significantly reduces tumor size in men with high-risk localized prostate cancer (PCa) and may decrease the risk of biochemical recurrence compared with leuprolide alone, according to a new study.

The study is the first to compare AAP plus leuprolide and leuprolide alone in this setting, according to a research team led by Eleni Efstathiou, MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center in Houston.

In a phase 2 open-label trial, Dr Efstathiou and colleagues randomly assigned 65 patients (median age 61 years) 2:1 to AAP plus leuprolide vs leuprolide alone for 3 months followed by radical prostatectomy. Even though they found no statistically significant differences in organ-confined disease, tumor volume measures were significantly lower in the combination therapy arm, and lower tumor epithelium volume correlated with significantly improved biochemical recurrence-free survival (RFS) after 4 or more years of follow-up. The 3-year RFS rate was 89% among men with a tumor epithelial volume of 0.3 cc or less compared with 61% for those with a volume greater than 0.3 cc, the investigators reported in European Urology.

Tumors pretreated with AAP plus leuprolide vs leuprolide alone had less proliferation and less androgen signaling expression compared with leuprolide alone.

Optimal therapy for high-risk localized prostate cancer remains an unmet need, Dr Efstathiou said. “The chance of its relapsing after localized definitive treatment are about 70%,” she said. “We observed that about 60% of men on the combined treatment arm had disease that was confined to the prostate,” she said. “We now have long-term follow-up and can verify that the men who achieved limited tumor volume following treatment remain disease free after median follow-up of 7 years. For prostate cancer, that would be the equivalent of a cure.”

The investigators also sought to identify potential biomarkers for AAP benefit or treatment resistance. They found that glucocorticoid receptor (GR) overexpression correlated with persistent tumors in the AAP plus leuprolide group. The presence of nuclear androgen receptor splice variant (ARv7) correlated with persistent tumors in both treatment arms. “We looked very closely for markers that could be associated with improved outcomes or resistance to treatment, Dr Efstathiou told Renal & Urology News. “This information has been instrumental for subsequent studies. We are currently actively looking at identifying such predictors of outcome in the original biopsies of these men with high-risk disease so that we can guide their treatment. We are confident that in the near future we will be able to propose curative strategies for high risk localized prostate cancer in a similar fashion as is standard of care in breast cancer. It is a unique opportunity to change the course of the disease and the lives of our patients with high risk localized disease ”

Dr Efstathiou and colleagues noted that GR activity previously had been identified as a potential resistance mechanism for AR inhibition in castration-resistant prostate cancer (CRPC) and this is the first report associating GR expression with resistance after AA treatment.

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Phase 3 trials are underway adopting the combination neoadjuvant strategy. The STAMPEDE study found that adding AAP to an LHRH analog prolongs progression free survival (PFS) and potentially overall survival (OS) in high risk localized disease when combined with radiation of the primary. “The combination is safe and very well known since this is an approved combination for more advanced prostate cancer. Is it prime time for urologist to adopt? Not yet, since we don’t really know which patients are the ones who are going to do best,” Dr Efstathiou said.

“This is a significant hypothesis generating paper identifying potential biomarkers such as Arv7 and GR activation in this high-risk patient population,” commented Leonard G. Gomella, MD, Chairman, Department of Urology, and Senior Director Clinical Affairs, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia. “Much longer follow-up and larger numbers of patients will be needed before this can be adopted as a standard of care,” Dr Gomella said.

Robert Dreicer, MD, Associate Director for Clinical Research and the Deputy Director of the University of Virginia Cancer Center, Charlottesville, Virginia, said much more follow-up is warranted and studies will need to have end points that include metastasis-free survival and OS. “The findings were modest, and this is clearly not yet ready for introduction into clinical practice. It remains an investigational construct,” Dr Dreicer said.

Emmanuel S. Antonarakis, MD, Associate Professor of Oncology at Johns Hopkins University in Baltimore, said the new findings are intriguing and support the view that more complete androgen suppression may lead to greater tumor regression, but more questions about neoadjuvant treatment with androgen deprivation plus abiraterone will need to be answered. “Planned neoadjuvant studies of this combination and other androgen-directed strategies are now being pursued in phase 3 trials, with more meaningful clinical end points such as metastasis-free survival,” Dr Antonarakis said.

Reference

Efstathiou E, Davis JW, Pisters L, et al. Clinical and biological characterisation of localised high-risk prostate cancer: Results of a randomised preoperative study of a luteinising hormone-releasing hormone agonist with or without abiraterone acetate plus prednisone. Eur Urol. 2019; published online ahead of print.

https://doi.org/10.1016/j.eururo.2019.05.010