Phase II results of SALV-ENZA Trial represent important step forward in optimizing SRT delivery

Presenting author:
Phuoc Tran, MD, PhD

By Amar U. Kishan, University of California, Los Angeles

Salvage radiotherapy (SRT) is a potentially curative therapy for many men experiencing a biochemical recurrence after radical prostatectomy. The addition of hormonal therapy (HT) to SRT has been shown to improve oncologic outcomes in both the NRG/RTOG 96-01 trial (which used two years of bicalutamide, a first-generation androgen receptor antagonist) and the GETUG-016 trial (which used six months of goserelin, a gonadotropin releasing hormone receptor agonist). However, HT has a host of adverse sequelae, including sexual dysfunction, adverse metabolic changes, decreases in bone mineral density and potentially cardiac morbidity. Thus, two major areas of further treatment optimization with regards to HT use with SRT readily present themselves: improved patient selection (e.g., with biomarkers) for intensification and improved alternatives to traditional HT. With regard to the former, PSA itself has emerged as an important biomarker, with the pre-SRT PSA acting as a predictive biomarker for intensification with HT. Transcriptomic tools, such as the Decipher genomic classifier, is also a promising candidate biomarker. High-level data supporting alternative HT agents are more scant.

In the multi-institutional phase II randomized SALV-ENZA trial (NCT02203695), Phuoc Tran, MD, PhD, and colleagues evaluate the safety and efficacy profile of the second-generation androgen receptor antagonist with SRT in men with high-risk prostate cancer who have recurred after prostatectomy. Enzalutamide is an attractive novel HT agent to study with SRT as it has been shown to improve survival in men with metastatic castration-sensitive and castration-resistant disease and is also thought to cause less adverse metabolic and skeletal events compared with traditional HT. The SALV-ENZA trial recruited patients who had pathological Gleason score 8-10 disease or Gleason score 7 disease with either pT3 disease or positive margins; pathological N0 status was required. Further, patients had to have a biochemical recurrence, defined as a rise in PSA above ≥0.05 ng/mL. Patients either received a placebo or 160 mg PO of enzalutamide daily for six months, with SRT delivered two months after beginning the drug. SRT consisted of 66.6-70.2 Gy to the prostate bed only. The primary endpoint of the trial was freedom-from-PSA-progression (FFPP), defined as the time from randomization to the date of PSA progression (generally requiring a 0.2 ng/mL rise above the post-SRT nadir). The power calculation suggested 96 patients were needed to identify a 20% improvement in two-year FFPP with 90% power.

Ultimately, 86 patients were randomized between April 2015 and February 2020, when the trial was closed as mandated by the sponsor; 90% of patients were white, and 9% were African American. The median baseline pre-SRT PSA level was 0.3. 65% of patients had extra-prostatic disease (pT3), 45% had Gleason sum 8-10, and 50% had positive surgical margins. The median follow-up was 34 months. Overall, two-year FFP was 87.1% with SRT+enzalutamide vs. 68.1% with SRT alone, corresponding to a HR of 0.40 (95%CI 0.17-0.92, p=0.03). Subgroup analyses demonstrate differential benefit (p-value of interaction=0.031) of ENZA in men with pT3 (HR 0.19, 95%CI 0.05-0.67) vs. pT2 disease (HR 1.29, 95%CI 0.34-4.81). Importantly, the most common adverse effects were grade 1-2 fatigue and urinary frequency, which did not differ significantly between arms. Grade 1 sexuality alteration was 23.3% with enzalutamide vs. 14.0% without it; for grade 2 events, the rates were 4.7% and 7.0% (the differences were not statistically significant). The only toxicities that were significantly increased with enzalutamide were breast/nipple pain and tenderness (grade 1 rates of 20.9% vs. 0%, and grade 2 rates of 4.7% vs. 0%) and nausea (grade 1 rates of 14% vs. 0% and grade 2 rates of 4.7% vs. 0%).

The findings presented by Dr. Tran are an important step forward in optimizing SRT delivery. Limitations include the small sample size, the fact that FFPP is not a surrogate for survival, and the short follow-up. The SALV-ENZA trial is nonetheless a double-blind, placebo-controlled, multi-institutional randomized trial and thus provides high-level evidence supporting the ability of a six-month course of enzalutamide to improve FFPP in a contemporary population of patients receiving modern SRT.

Perhaps most importantly, the data support the safety profile of enzalutamide as a monotherapy. Ultimately, however, larger studies are needed to explore the true oncologic benefit of enzalutamide (or any second-generation agent) to SRT. In this regard, the results of the NRG GU006 (NCT03371719) randomized phase II study, which randomized 311 men with recurrent disease after radical prostatectomy to SRT plus placebo versus SRT plus apalutamide (another second-generation androgen receptor antagonist) are eagerly anticipated. Notably, stratification by the mRNA-based PAM50 genomic classifier was performed. Other trials, such as NRG/RTOG 3506 (NCT03809000) and FORMULA-509 (NCT03141671), are exploring whether further intensification of traditional androgen deprivation therapy with second-generation agents will be of oncologic benefit in SRT. Translational correlative studies from all of these trials will facilitate biomarker identification to ultimately improve personalization of treatment intensification.

Abstract 159 – Phase II Randomized Study of Salvage Radiation Therapy (SRT) plus Enzalutamide or Blinded Placebo for High-Risk PSA-Recurrent Prostate Cancer after Radical Prostatectomy: The SALV-ENZA Trial was presented on October 24, 2022, during the SS 11 – GU 2 – New Insights into Post-Prostatectomy Radiotherapy session at the 2022 ASTRO Annual Meeting.