SALV-ENZA Trial: Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy Journal Club - Christopher Wallis & Zachary Klaassen

January 12, 2023

In this UroToday Journal Club Christopher Wallis and Zachary Klaassen highlight the Journal of clinical oncology publication of the phase II SALV-ENZA Trial which sought to investigate whether enzalutamide, without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen progression when combined with salvage radiation therapy in men with recurrent prostate cancer after radical prostatectomy.


Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Chris Wallis: Hello, and thank you for joining us for a UroToday Journal Club discussion. Today we're talking about the recently published SALV-ENZA trial, a Phase II randomized study of salvage radiation therapy plus enzalutamide or placebo for high-risk PSA recurrent prostate cancer after radical prostatectomy. I'm Chris Wallis, an assistant professor in the division of urology at the University of Toronto. With me today is Zach Klaassen, assistant professor in the division of urology at the Medical College of Georgia. You can see here the citation for this recent publication of the Journal of Clinical Oncology. Among men who die of prostate cancer, nearly all progressed mCRPC before their death. However, the majority of these men were initially diagnosed with localized disease and had subsequent disease recurrence and progression. Typically, the first recurrence event following local therapies, biochemical recurrence with evidence of a rising PSA in the absence of radiographically detectable metastases.

For men who are initially treated with surgery, that is radical prostatectomy, patients with biochemical recurrence remain curable with salvage radiotherapy. Salvage radiotherapy can improve biochemical control and may prevent the development of metastatic disease as well as death. Outcomes from salvage radiation are optimized when patients receive it early following their biochemical recurrence, that is with a low PSA. Treatment intensification has become a standard across many disease states in prostate cancer. The androgen receptor is known to drive growth in most prostate cancer tumors, and as a result, ADT is a mainstay of therapy. In addition to inducing apoptosis or senescence of cancer cells, ADT provides radiosensitization. Two randomized controlled trials have investigated the benefit of adding androgen deprivation therapy to salvage radiation showing the clinical benefit. We look at one of these trials, the NRG/RTOG 96-01 trial, which demonstrated that high dose by bicalutamide demonstrated a survival benefit when added to salvage radiation therapy.

However, there are important limitations in terms of both toxicity with cardiovascular and neurologic events, as well as subsets of patients who did not appear to benefit, namely those with low PSA levels. As a result, there's considerations regarding alternative ways to target the androgen access. We know that agents such as enzalutamide and other second generation androgen receptor blockers have become widespread in other prostate cancer disease states, including mCRPC, mCSPC, nmCRPC. Further, enzalutamide monotherapy, as studied in the ENACT trial, has been suggested to preserve quality of life compared to use of enzalutamide with standard androgen deprivation. In this study, the authors performed a multi-center randomized Phase II trial in seven U.S. Institutions enrolling men with biochemical recurrence following radical prostatectomy. This was defined as one rise in PSA above a baseline undetectable level. Patients were included if their age 18 years and older, had prostate adenocarcinoma, and were primarily treated with radical prostatectomy.

They had to have Gleason score of eight to 10 or Gleason score of seven with pT3 disease or positive surgical margins. They had to have pathologically uninvolved lymph nodes and no radiographic evidence of recurrence. In terms of inclusion, they had to have biochemical recurrence with an absolute PSA of at least 0.07 and a testosterone that was not castrate. They couldn't have any prior hormonal therapies and had to have a good ECOG performance test as well as life expectancy. In terms of exclusion criteria, patients with active secondary cancers, those who had primary radiation therapy, are concurrent users of anti-androgens, estrogens, 5-alpha reductase inhibitors, or other anti-cancer agents were excluded. Additionally, patients with treatment using systemic corticosteroids or those with a history of seizures were further excluded. Once included, patients were randomly assigned in a one-to-one fashion to receive either enzalutamide or placebo, and randomization was stratified according to center, a level of PSA prior to salvage therapy, and pathologic Gleason score.
Patients were treated with a six-month treatment encompassing 180 days of either enzalutamide or matched placebo. Adherence was monitored using a pill count. Salvage radiotherapy was started on day 61 with relatively standard dose and fractionation approaches. Follow-up was performed every 30 days with clinical examination, adverse event assessment, laboratory investigations, and quality of life questionnaires. There was further exploratory analysis of tissue specimens with transcriptome profiling using the Decipher assay, and the radical prostatectomy specimens were leveraged for this genetic and genomic assessment. The highest grade tumor focus was identified based on the radical prostatectomy specimen, and macrodissection was performed prior to RNA extraction. The primary outcome was freedom from PSA progression. This was defined as the time from randomization until PSA progression or the last measurement. Patients who achieved a PSA less than or equal to 0.1 following salvage therapy, PSA progression was defined as a PSA of at least 0.2 with a second confirmatory rising PSA level.

For patients who did not achieve an undetectable PSA, PSA progression was defined as a PSA increase of at least 0.2 from their nadir confirmed with a second rise at least eight weeks later. Secondary outcomes included local recurrence within the radiation field, metastasis-free survival, as well as safety, feasibility, and tolerability. The primary analysis was based on the attention to treat principle with the Kaplan Meier technique used to assess freedom from PSA progression. Cox proportional hazards models were used to estimate the hazard ratio of PSA progression for patients treated with enzalutamide versus placebo accounting for surgical margin status on baseline PSA and pathologic Gleason score.

Subgroup analyses were performed according to pT stage, margin status, Gleason score, baseline PSA, age, and race. The authors designed this trial with an anticipated 20% absolute improvement from 20... Oh, sorry. From 60 to 80% over two years corresponding to a hazard which was 0.44, utilizing a power of 90% and a one-sided alpha of 0.1, 39 PSA-progression events were required, and thus the authors accrued 96 patients. However, this was not met, and therefore the trial was terminated early without full accrual. Now, going to hand over to Zack to walk us through the results of the SALV-ENZA trial.

Zach Klaassen: Thanks so much for that great introduction, Chris. This is the CONSORT diagram of the SALV-ENZA trial. We can see here that there was 162 patients that were assessed for eligibility. Ultimately, 86 were randomly assigned, including 43 to the SALV-ENZA trial or arm, and 46 to the placebo arm. Ultimately these patients were included in the intention to treat analysis. This table looks at the baseline characteristics of the SALV-ENZA trial, and you can see here that the majority of these patients were accrued at Johns Hopkins University as well as OHSU. The median age at randomization was well-balanced between these two groups with median age of 69 in the ENZA group and 66 in the placebo group. Pathological T stage was most commonly T3 at roughly two thirds of patients and roughly half of patients had a positive surgical margin.

With regards to the radical prostatectomy Gleason score, these were also well-balanced with roughly 20 to 30% Gleason 4+3, roughly one quarter Gleason 8, and between 16 and 25% Gleason 9. The median pre-treatment PSA for these patients was 0.3 in both arms of the trial. This is the Kaplan-Meier curve looking at freedom from PSA progression by stratification of enzalutamide versus the placebo arms. We can see enzalutamide plus salvage radiotherapy in blue and placebo plus salvage radiotherapy in red. We see that there was a hazard ratio favoring enzalutamide plus salvage radiotherapy of 0.42, 95% confidence interval of 0.19 to 0.92. Additionally, the two-year freedom from PSA progression rates was 84% for enzalutamide and 66% for placebo. This is the forest plot of the subgroup analysis for freedom of PSA progression, and I've highlighted in the blue box several important findings.

We see here that patients that were T3 compared to T2 had a significant benefit from enzalutamide, T3 patients with a hazard ratio of 0.2, and those with a positive surgical margin also had a benefit compared to those with a negative surgical margin with a hazard ratio of 0.14. We can see here very little variability in terms of treatment site, Gleason score, baseline PSA, and age. This is the common adverse events by grade and treatment arm. You can see this broken down by Grade 1 and Grade 2. I've highlighted with asterisks on the left several of the important adverse events, specifically highlighting adverse events for enzalutamide. We see breast and nipple pain or tenderness, Grade 1, 20.9%, and Grade 2, 4.7%. Nausea, Grade 1, 14% for enzalutamide and 4.7% Grade 2 for enzalutamide for nausea. This figure highlights that serum testosterone levels were elevated during the six months of enzalutamide treatment. As we can see here, nearly up to roughly 800, but then decreasing again after this completion of the enzalutamide portion of the trial.

This is the forest plot of gene expression signature subgroup analysis specifically for freedom from PSA progression. As Chris mentioned, this was done by the Decipher score. One significant point to highlight here is that earned positive alterations were significantly... They significantly benefited with treatment of enzalutamide with the hazard ratio of 0.11, 95% confidence interval of 0.01 to 0.90. Generally, the other components of the genomic scores, specifically p53, RB, and PAM50 did not have any variation when assessed for PSA progression. Several discussion points from the SALV-ENZA trial. This is the first trial to test the efficacy of next generation AR blockade with salvage radiotherapy in men with biochemical recurrence after radical prostatectomy. We can see here that with six months of enzalutamide plus salvage radiotherapy without ADT, it was an 18% absolute benefit in two-year freedom from PSA progression. There was a 58% relative improvement in freedom from PSA progression, and there was a differential benefit of enzalutamide in men that had pT3 or surgical margin positivity.

There is differences between SALV-ENZA and other randomized controlled trials of hormonal therapy plus salvage radiotherapy. This includes other trials such as NRG 96-01 16, GETUG-16, and NRG/RTOG 05-34. First, this was patients with more contemporary pre-salvage radiotherapy PSA levels. Secondly, this was a modern radiotherapy dose and techniques for salvage radiotherapy that were employed. Thirdly, only six months of enzalutamide were used versus two years of high dose blut. In RTOG 96-01. Fourth, this included only men with pN0 prostate cancer and only treated the prostate bed compared to RT0G 05-34, which tested the question of elective nodal radiation. Finally, SALV-ENZA tested enzalutamide without ADT plus salvage radiotherapy versus GETUG-16 and RTOG 05-34 which used ADT. There's several important ongoing randomized trials that are testing next generation AR inhibitors in a similar fashion to SALV-ENZA. First, this includes the BALANCE NRG's GU006 trial, which is Phase 2 study randomizing men with biochemical recurrence of salvage radiotherapy plus placebo versus salvage radiotherapy plus apalutamide stratified by the PAM50 genomic classifier.

Secondly, the STEEL trial of RTOG 3506 is a Phase 2 study randomizing man with biochemical recurrence to salvage radiotherapy plus ADT versus salvage radiotherapy plus ADT plus enzalutamide. Finally, the FORMULA-509 trial is a Phase 2 study randomizing men with biochemical recurrence with salvage radiotherapy plus ADT versus salvage radiotherapy plus ADT plus abiraterone or apalutamide. In conclusion, the SALV-ENZA trial demonstrates that salvage radiotherapy plus enzalutamide monotherapy for men with PSA recurrent high-risk prostate cancer after prostatectomy was safe and delayed PSA progression relative to salvage radiotherapy alone. However, these data are insufficient at this point in time to change clinical practice. Finally, the impact of enzalutamide on distant metastasis or survival is unknown and should be explored in further in a larger trial, ideally also addressing the incremental benefit of the addition of androgen deprivation therapy. But thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussion of the SALV-ENZA trial recently published in the Journal of Clinical Oncology.