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Christopher Wallis: Hello, and thank you for joining us for UroTODAY Journal Club. Today, we are discussing a recent publication entitled 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer, the EMPIRE-1 study. This is a single-center, open-label phase 2/3 randomized controlled trial.

I'm Chris Wallace, a Fellow in Urologic Oncology at Vanderbilt. With me today is the Assistant Professor in the Division of Urology at The Medical College of Georgia, Zach Klaassen. And this is the citation for this recent publication by Dr. Jani and published in The Lancet.

As you can see highlighted here, there have been a number of trials over the years, assessing the role of adjuvant radiotherapy in patients with prostate cancer. The vast majority of these, including all of the studies on this current slide, assessed adjuvant radiotherapy in comparison to a variety of known standardized treatment approaches.

And when we pool these together, we can see that adjuvant radiotherapy improves biochemical progression-free survival, as well as local regional recurrence-free survival, but the effects on metastasis-free survival and overall survival are much less clear and potentially not beneficial. As a result, in spite of the number of trials, which have assessed adjuvant radiotherapy and this approach is not widely adopted,  instead, salvage radiotherapy is much more commonly used. And recently we've seen a number of randomized trials, including the RADICALS-RT study, the GETUG-AFU 17 study, and the RAVES study, which were then synthesized in the ARTISTIC collaborative, which demonstrated that the use of early salvage radiotherapy rather than adjuvant radiotherapy may be at least as good, if not better. And so, however, among patients who receive postoperative radiotherapy, inadequate response or lack of total eradication of prostate cancer is not uncommon affecting 20% to 60% of patients.

And the hypothesis here is that improved characterization of the disease-burdened patients prior to their radiotherapy may improve outcomes following radiotherapy. And so in order to identify disease burden more accurately, these authors sought to use novel radiotracers, namely 18F-fluciclovine, which is a synthetic amino acid PET radiotracer. And in restaging patients who had recurrent cancer, this is proven to outperform conventional imaging, typically a CT or MRI as well as a bone scan. And so the hypothesis that is tested in EMPIRE-1 is that if patients are appropriately selected for salvage radiotherapy with 18F-fluciclovine radiotherapy will be more effective and have better disease control.

And to do this, they enrolled patients on an open-label, single-center Phase 2/3 randomized controlled trial, including men who had prostate cancer and a detectable PSA following prostatectomy. They had to have no evidence of metastatic disease on conventional imaging using bone scan and CT or MRI, and ADT was allowed in the study, as long as PSA remained detectable while on ADT. Patients were excluded if they had a performance status of three or worse, had prior pelvic radiotherapy or contra-indications to radiotherapy, had a prior non-prostate event, invasive cancer, or severe acute morbidity, which would preclude the use of our radiotherapy.

The radiotherapy decision was made prior to randomization. And this included both the decision to offer radiotherapy as well as the radiotherapy field used and the plan for whether ADT can be used concomitantly, and if so, how long. Patients were then randomized in a one-to-one fashion to receive radiotherapy, which is directed by conventional imaging or radiotherapy directed by conventional imaging in addition to fluciclovine PET/CT. Randomization was done according to a permuted block design with stratification, according to a PSA at the time of randomization, the presence of adverse pathology radical prostatectomy, and the intent for ADT.

And so, to characterize, these patients all received conventional imaging using bone scan and CT or MRI. And in addition, those who were randomized to receive axumin PET/CT underwent this according to the standard Emory protocol, which was evaluated with the semi-quantitative analysis and visual analysis using a 5-point Likert scale.

And so in the control group who received conventional imaging alone, decisions regarding therapy were based according to the pre-therapy features, radical prostatectomy pathology, and PSA dynamics. And radiotherapy was given to the prostate bed with, or without pelvic radiotherapy at the discretion of the physician. In the experimental group, treatment decisions were a bit more protocolized according to the PET/CT results. For those who had extra pelvic or evidence of bony disease, radiotherapy was not offered on the basis of a proven systemic spread. For patients who had pelvic nodal disease, pelvic radiotherapy, in addition to prostate bed radiotherapy was offered. Whereas for those who had a prostate bed uptake or no uptake at all, only prostate bed radiotherapy was offered and pelvic radiotherapy was spared. PET/CT was there for used to guide this treatment plan. And ADT, where utilized, was done in the form of GnRH agonists, with or without anti-androgen, which was given concurrently with radiotherapy for up to six months in duration.

Patients were followed in the clinic and with PSA testing, which was performed at 1, 6, 12, 18, 24, 30, and 36 months. And for those who were receiving Androgen Deprivation Therapy, in addition to this PSA testing, serum testosterone and liver function testing were also performed. The primary endpoint was 3-year event-free survival. And events were defined as a PSA of 0.2 nanograms per milliliter above post-radiotherapy nadir, a persistent PSA, evidence of imaging or clinical failure, or the start of other systemic therapy. Secondary endpoints included a comparison of pre and post PET treatment decisions as well as acute and late GI and GU toxicities.

In terms of sample size, the authors calculated that 146 patients in total comprising 73 per arm give the ability to detect the 20% difference between the two groups, which they had hypothesized would be 50% in conventional imaging and 70% in the axumin informed arm for 3-year event-free survival.  Adjusted for a 10% withdrawal and dropout, this led to a target of 162 patients. Changes in clinical decision-making were assessed using the Clopper-Pearson method with the binomial analysis. And 3-year event-free survival was assessed using the Zed test, and the Kaplan-Meier technique was used, as well as Cox Proportional Hazards models to assess event-free survival.

Now, I'm going to hand it over to Dr. Klaassen to walk us through the results of the EMPIRE-1 trial.

Zachary Klaassen: Thanks, Chris. So this is the study design, which you can see here. There were 165 patients enrolled and randomly assigned, 82 allocated to the conventional imaging group and 83 allocated to the Axumin PET/CT group. One withdrew from the conventional imaging group and three withdrew from the fluciclovine group, leading to 81, receiving radiotherapy in the conventional imaging group and 76 receiving radiotherapy in the Axumin PET/CT group.

These are the baseline characteristics of these patients. On the right is the Axumin PET/CT group with 83 patients. To the left of that group is the conventional imaging group at 82 patients with a comparable age of 61 years of age in each group. The majority of patients were Caucasian at 63% in each group with actually a decent enrollment of African-Americans, including nearly one-third of patients in each group. The PSA before radiotherapy in each group was similar at 0.34, extracapsular extension was 52% in the conventional group and 47% in the Axumin group. The margin positivity was 50% in the conventional group and 45% in the Axumin group. In terms of patients that had any ADT therapy, 35% in the conventional group and 38% in the Axumin group. In terms of long-term use of ADT, defined as 18 to 24 months, 10% of patients in the conventional imaging group and 11% of patients in the Axumin PET group.

This is the primary endpoint of 3-year event-free survival. The red line is the Axumin PET/CT group. And the blue line is the conventional imaging group. And looking at the hazard ratio with the Axumin PET/CT group, as the reference, the hazard ratio is 1.84 with a 95% confidence interval of 0.98 to 3.47, Log-rank P-value of 0.0540. As you can see here, the 3-year event-free survival rate for conventional imaging was 63%. And for the Axumin group was 75.5% with a significant P-value of 0.0028.

This is the Cox Proportional Hazard model. You can see the variables on the left, the comparison group listed here, and focusing on the multi-variable model, I have highlighted the significant variables with asterisks. And you can see that a PSA of greater than one compared to less than one, the hazard ratio of 3.49, and a 95% confidence interval of 1.76 to 6.90. In terms of extracapsular extension, no versus yes, the hazard ratio of 0.45 and a 95% confidence interval of 0.21 to 0.95. At the bottom of this table, prostate bed and pelvis radiation versus prostate bed alone, the hazard ratio of 2.09, 95% confidence interval of 1.07 to 4.08. And finally, the study group, conventional imaging versus Axumin PET/CT guided therapy, the hazard ratio of 2.04 and a 95% confidence interval of 1.06 to 3.93.

This table looks at the summary of clinical decision-making and overall there was a pre versus post-PET decision change rate of over one-third of patients at 35.4%. So breaking down this table a little bit further, patients that were pre-PET decision prostate bed only compared to post-PET where they stayed the same at prostate bed only therapy, 31 out of 79 patients. In terms of treatment de-intensification pre-PET decision, prostate bed and pelvis, and final decision after PET/CT of prostate bed only, 10 out of 79 patients. Patients that had treatment intensification in terms of prostate bed only pre-PET decision and post-PET decision of prostate bed plus pelvic radiation, 14 out of 79 patients. And patients that had a pre-PET decision of prostate bed plus pelvis radiation who ultimately underwent that therapy was 20 out of 79. Finally, looking over here, patients who had a pre-PET decision of prostate bed plus pelvis radiation, but ultimately had no radiation after their PET/CT scan 4 out of 79 patients.

These tables look at the provider-reported toxicity. The top two tables look at acute GU toxicity.  At the very top, and below that acute GI toxicity, followed by late GU toxicity,  at the bottom of the table, late GI toxicity. And in summary, all of these between the two arms had no significant difference in toxicity comparisons between these groups.

So, several discussion points from the EMPIRE-1 trial, this inclusion of Axumin PET/CT into the decision-making process for radiotherapy after prostatectomy seemed to reduce the likelihood of recurrence or inadequate response to treatment in those men without evidence of extra pelvic disease, based on conventional imaging. Looking at this in more detail radiotherapy after prostatectomy is ideal for introducing new imaging studies because of three factors, including the limitations of conventional imaging, the high potential clinical impact of increased precision in decision-making and treatment guidance, and the availability of a sensitive biomarker such as PSA for followup.

Advances in systemic therapy are being studied in the setting of disease progression or inadequate treatment response after prostatectomy with radiotherapy with several ongoing randomized control trials as listed here, including the NRG Oncology GU 002 study looking at docetaxel, the GU 006 study looking at apalutamide, the GU 008 study looking at abiraterone and apalutamide, and finally, the RTOG 3506 study looking at enzalutamide.

So, in conclusion, the inclusion of 18F-fluciclovine-PET into post-prostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Finally, the integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussion looking at the EMPIRE-1 study.