Intense androgen deprivation therapy (ADT) prior to radical prostatectomy (RP) in locally advanced prostate cancer may result in favorable pathologic responses in some patients, according to the findings of a new phase 2 study.1

Multiple investigators led by Rana R. McKay, MD, of the University of California San Diego, compared the use of neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) prior to RP for locally advanced prostate cancer (PCa) in a 2:1 randomization. The rate of pathologic complete response (pCR) or minimal residual disease (MRD) was 16% in the EL group compared with 30% among ELAP recipients, a difference that was not statistically significant.

Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at the time of RP.

“Although efficacy is not proven, neoadjuvant therapy combined with RP holds promise for men with poor prognosis prostate cancer,” Dr McKay and colleagues concluded in the Journal of Clinical Oncology.

Dr McKay’s team studied 75 patients with locally advanced PCa (Gleason score of 4 + 3 = 7 or greater, PSA level greater than 20 ng/mL, or T3 disease). All patients had lymph nodes smaller than 20 mm. Investigators randomly assigned 50 men to receive ELAP (abiraterone 1,000 mg/day, enzalutamide 160 mg/day, leuprolide 22.5 mg every 12 weeks, and prednisone 5 mg/day) and 25 to receive EL (enzalutamide (160 mg/day plus leuprolide 22.5 mg every 12 weeks) for 24 weeks followed by RP. (Clinical trial information: NCT02268175).

The men were enrolled at 4 centers, and 65 (87%) had high-risk disease by National Comprehensive Cancer Network criteria. The treatment arms did not differ significantly with regard to rates of ypT3 disease, positive margins, and positive lymph nodes. The treatments were well-tolerated.

Commenting on the new study, Gurkamal Chatta, MBBS, professor of oncology and clinical chief of genitourinary medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, told Renal & Urology News that the findings open a window into developing strategies for better molecular characterization and targeting of patients who present with high-risk disease at diagnosis. The non-significant difference in the rates of pCR or MRD between the treatment arms suggests the study was likely underpowered, he said.

“I and others keenly await data on the clinical significance of pCR and MRD in prostate cancer with longer-term follow-up, as well as biomarker data that will help us to predict response/resistance to disruption of the AR axis,” Dr Chatta said.

“The treatment approach of androgen deprivation therapy prior to prostatectomy tested by the authors certainly has the potential to meaningfully improve clinical outcomes, such as patient survival, in patients who currently may not be successfully cured using standard therapy alone,” commented Kevin T. Nead, MD, a radiation oncology resident at the Hospital of the University of Pennsylvania and an associate fellow in the Leonard Davis Institute of Health Economics, both in Philadelphia.

The study demonstrated that 2 overlapping ADT regimens prior to RP are safe and result in favorable pathologic responses at the time of surgery, Dr Nead said. The study was not designed to evaluate whether ADT prior to RP improves clinical outcomes such as survival, but the authors initial findings are promising and deserve further study in larger randomized trials comparing this combination therapy to standard of care therapy.

“Given that many men with intermediate-risk and high-risk prostate cancer will not be cured of their disease using current standard of care therapy alone, clinical trials that investigate how to improve current patient outcomes, such as by administering androgen deprivation therapy prior to prostatectomy, are critical.”

“This study provides promising news in that it demonstrates that these medications given in the neoadjuvant setting do not increase operative complication rates and are associated with a 30% pathologic CR rate in patients with maximal hormonal ablation/blockage,” said Robert G. Uzzo, MD, professor and chairman of the department of surgery at Fox Chase Cancer Center in Philadelphia. Dr Uzzo, who serves as medical director for urology at Renal & Urology News, noted that recent evidence has demonstrated that the ability to dial down endogenous testosterone levels below previously defined castrate levels improves outcomes in the pre- and post-chemotherapy hormone refractory metastatic setting and now even in the non-metastatic castrate resistant setting. “This study is a logical extension of these beneficial findings later in the disease state and offers an intriguing glimpse into potential benefits of preoperative treatment in high risk surgically eligible men.”

The new study also identifies potential biomarkers associated with more extensive residual disease. Residual tumors in the 2 arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. However, tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. “While the news is promising, it doesn’t yet demonstrate the ultimate aim which is improved cause-specific survival and OS. Nonetheless, it provides the basis for larger scale trials on the topic of neoadjuvant therapy in high-risk prostate cancer, a space up until now has remained unyielding.”

Reference

1.     McKay RR, Ye H, Xie W, et al. Evaluation of intense androgen deprivation before prostatectomy: A randomized phase II trial of enzalutamide and leuprolide with or without abiraterone. J Clin Oncol. 2019; published online ahead of print.

doi: 10.1200/JCO.18.01777