Christopher Wallis: Hello. And thank you for joining us here, it's UroToday Journal Club discussion. Today, we're discussing a recent publication entitled Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastasis in the UK, the PROMPTS trial: An open-label, randomized, controlled phase 3 trial. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication in Lancet Oncology, led by Dr. Dearnaley.

Spinal cord compression is one of the more devastating outcomes of a metastatic cancer diagnosis. It has profound effects on functional status and patients' quality of life. Now early identification of spinal cord compression is critical, as the neurologic function a patient has prior to their treatment is a important predictor of their long-term outcome. In metastatic castration-resistant prostate cancer, the metastatic disease burden predominantly affects the skeleton. And a substantial burden of the disease is due skeletal-related events, of which spinal cord compression is the most clinically significant. Estimates of spinal cord compression range from 7% to 24% to ... depending on the quoted study, and early radiologic signs may be found in between one quarter and one third of asymptomatic patients with mCRPC.

The goal of this study was to assess the role of screening MRI to detect radiologic evidence of spinal cord compression with subsequent pre-emptive treatment in men with mCRPC. This is a multicenter parallel-group, open-label randomized controlled phase 3 trial they've performed in 45 NHS hospitals. The authors enrolled men who had either a pathologic diagnosis of prostate adenocarcinoma or a clinical diagnosis which comprised evidence of osteoblastic bone metastasis in a PSA level exceeding 100 nanograms per milliliter. Patients had to have asymptomatic spinal metastasis and CRPC with an absolute PSA level of at least 5 nanograms per milliliter. Finally, patients had to have the ECOG performance status of 0 or 2. Patients were excluded if they had the presence of back pain or neurologic symptoms, had previously undergone spinal MRI, had prior radiotherapy to the vertebrae, spinal surgery for spinal cord compression or any contraindication to an MRI.

Patients after enrollment were randomized in a 1:1 fashion to receive either no MRI as a control group or screening MRI as the intervention. Allocation was performed centrally using a minimization algorithm. And balancing factors included the treatment center, ALK level, and number of previous systemic treatments. The presence of prior spinal surgery or radiotherapy, and whether a CT or PET-CT had been performed in their preceding 6 months. There was no masking, given the infeasibility of a sham MRI.

Spinal MRI in the intervention group was performed within 4 weeks of randomization. A spinal coil was used, and the minimum field strength was 1.0 Tesla. Spinal images were acquired from the base of the skull to coccyx, with both T1 and T2 weighted images. These were assessed by a local radiologist using a 7-point epidural spinal cord compression scoring system, and each vertebrae was individually assessed on this scale. Epidural disease in the absence of symptoms was defined as radiographic spinal cord compression, whereas epidural disease in the presence of symptoms was deemed clinical spinal cord compression. Where screening MRI was positive for radiographic spinal cord compression, pre-emptive treatment with either radiotherapy or surgical decompression was recommended. And after treatment, patients were, received a follow-up MRI every 6 months.

At baseline, patients underwent investigations of their medical history, laboratory investigations, neurologic assessment and patient-reported outcome questionnaires. Following their MRI, patients were screened for serious adverse events in the 24-hour window using the CTCAE v4. They were then followed at 3-monthly intervals for 2 years, and then at 30 and 36 months. Neurologic status was assessed using the Frankel score, and patients also performed the patient-reported outcome battery. Where any patient did in either the intervention or control arm developed new neurologic symptoms, consistent with a clinical spinal cord compression, a spinal MRI was performed. All radiographic evidence of spinal cord compression was treated with radiotherapy or surgery, whereas clinical spinal cord compression was treated according to NICE guidelines.

The primary outcome was the incidence of and time to confirmed clinical spinal cord compression. This was defined as a compromised Frankel score. And you can see here that this is Frankel scores A through D, with supportive radiologic findings. Any diagnostic uncertainty was resolved with central review. Secondarily, the authors looked at rates of detection of a radiographic spinal cord compression when screening MRI. The 1 and 2-year incidence and time to functional neurologic deficits and irreversible neurologic deficits, the 1-year incidence of any spinal cord compression, overall survival, cost effectiveness, pain, and patient-reported outcomes. As Zach will show, the results of the study precluded eventual cost effectiveness analysis.

The authors performed a power calculation assuming a 1-year rate of clinical spinal cord compression of 15.6% in the control arm with an assumption of a baseline radiographic spinal cord compression prevalence of nearly 13%, assuming all these patients, as well as 3.2% of non-radiographic spinal cord compression patients would develop clinical evidence of spinal cord compression within 1 year without treatment. The authors then assumed a hazard issue of 0.48 and used an alpha of 0.05 and beta of 0.10, and to calculate a targeted sample size of 541 patients. Subsequently they reduced their power from 90% to 85%, with an increase in their beta from 0.1 to 0.15, to allow for completion of accrual. A formal pre-planned analysis was conducted after 54 patients were enrolled in the intervention group and had undergone MRI, this analysis allowed for ongoing recruitment if the rate of radiographic spinal cord compression was at least 10%. All analyses performed in this study were done according to the intention-to-treat population.

The authors compared incidence of clinical spinal cord compression and functional neurologic deficit using the CIR, using Gray's test to compare between groups. And sub-distribution hazard ratios were calculated using models adjusting for the balancing factors as well as time since CRPC diagnosis and time since continuous ADT, as well as a natural log of PSA and performance status. Cause-specific regression models were used, with death treated as a competing risk. The incidence of radiographic spinal cord compression at screening was calculated using binomial proportions, with logistic regression models used to identify clinical predictors of the evidence of radiographic spinal cord compression. The authors perform comparisons between screen-negative and control populations as a sensitivity analysis, as all screen-positive patients had spinal cord compression at least radiographically at baseline. The authors further performed post-hoc analyses of the time to new systemic therapy.

Finally, patient-reported outcomes were scored in keeping with their manuals and cross-sectional analyses of these PROs were performed at each time point until 24 months. The 12-month analysis was deemed the primary time point of interest, and the arms were compared using the Mann-Whitney U test. In the case of these patient-reported outcome metrics, due to the multiple comparisons used, an alpha of 0.01 rather than 0.05 was used to denote statistical significance. At this point in time, I'm going to hand it over to Zach to walk us through the results of the PROMPT trial.

Zach Klaassen: Thanks so much, Chris. So, this is the trial profile for the PROMPTS trial. As we can see here, there was 422 men that were randomly assigned, 210 to the control group and 210 to the intervention group. Ultimately in the control group, 47 men died by 12 months, with 161 men still follow upped at 12 months. And 210 men included in the ITT population. On the right is the intervention group, 210 patients in this arm. 9 did not have a screening MRI. 201 subsequently had a screening MRI, 61 which were positive for radiographic spinal cord compression. And we can see at the bottom here 168 were still followed up at 12 months, with all of these patients as well included in the ITT population.

This is the baseline characteristics for the study. And we can see here that the intervention group was on the right and to the left of that is a control group, with balanced age at randomization of 74 years, with a median time to randomization from initial diagnosis in the control group of 4.4 months and 4.2 months in the intervention group. Moving down to the metastatic disease at diagnosis, 62% in the control group and 59% in the intervention group. The serum PSA at the time of randomization was actually a little bit higher in the control group, at 62, and it was 40 in the intervention group. And we can see that the majority of these patients were ECOG 0 or 1. In terms of sites of metastases at randomization, bone metastases and essentially everybody, with about one fifth of the patients also having lymph node metastases.

With regards to initial first-line hormone therapy, LHRH analogs in roughly 85% of patients. Number of second-line treatments, most commonly 2-3, at about 40% to 48%. But even one third of patients having greater than or equal to 4 treatments in both arms prior to randomization. When we look at the types of treatments that these patients had, moving to the right part of this panel, second-generation endocrine therapy about 40% to 45% of patients, about one third of patients receiving chemotherapy prior to randomization. Interestingly, about 15% to 20% of patients had back pain at the time of randomization, in both of these groups.

This figure looks at the ESCC vertebra level scores at screening and follow-up spinal MRI scans. We can see on the left, this is at 6 months. And to the right of this, this is at 12 months. Where you can see this diagonal line for each of these chart ... or each of these figures, and patients to the left of this had an improvement in score at the time of 6 or 12 months. I've also listed some summary points for these figures, as follows on the right. So among 73% of patients screen-positive, treated with radiotherapy that were alive at 6 months time, at the time of 6 months 57% of assessable and treated metastases with radiographic spinal cord compression had improved scores. 39% were stable, and 4% of lesions progressed. Also at 6 months, of note, there were 21 new sites of radiographic spinal cord compression in 8 patients. At 12 months, in among 21 patients, 80% of treated sites with radiographic spinal cord compression had improved scores. 15% were stable, and 4% had progressed.

This is the cumulative incidence of clinical spinal cord compression, which was the primary outcome for this study. The control patients are in blue and the intervention patients are in pink. And we can see that there was no difference in the cumulative incidence of clinical spinal cord compression, with a hazard ratio of 0.64 and a 95% confidence interval of 0.37 to 1.11. This is the cumulative incidence of persistent neurologic functional deficit, again no difference. We can see at 12 months the cumulative incidence for the control group was 5.7%, in the intervention group was 2.9%. And at 24 months in the control group, there was 11.2% with persistent neurological functional deficit compared to 7.3% in the intervention group with a Gray's test p-value of 0.070.

This is the Kaplan-Meier plot of overall survival. No difference in the survival between these two arms, with an unadjusted Cox regression model hazard ratio of 0.98 and a 95% confidence interval of 0.79 to 1.21. This final figure in the results is the post-hoc analysis of time to first additional post randomization treatment. On the left and we can see the plot for new hormonal therapy and new radioisotope therapy, with no difference between these two groups. However, on the right side we see the plot for new chemotherapy and any new systemic treatment. And there was an improvement in time to these two outcomes, for the patients in the intervention group of spinal MRI.

So several discussion points from this important PROMPTS trial, this is the first randomized trial to assess the role of screening using spinal MRI to detect and treat radiographic spinal cord compression and metastatic prostate cancer. As we discussed, there was no significant reduction in the proportion of patients with clinicals spinal cord compression at 12 months, with a difference in cumulative incidence between the control and intervention group of 2.4%. Radiographic spinal cord compression was identified in 31% of patients with assessable screening MRIs. And despite the substantial incidence of radiographic spinal cord compression, the development of clinical spinal cord compression in both study groups was lower than anticipated with 6.7% in the intervention group compared to 4.3% in the control group. However, more imaging and radiotherapy resources were used in the intervention group compared to the control group. This may be offset by decreased use of new systemic treatments and possible reduction in persistent neurological functional deficits in the intervention group.

So in conclusion, this study found reproducibility of an ESCC scale, which is thus recommended for widespread adoption in the oncology practice. There was no significant difference in the incidence of clinical spinal cord compression or irreversible neurological function between the MRI-screened intervention group and the control group. Particular vigilance is recommended for these patients, with a low threshold for recommending a spinal MRI if any new back pain manifests because these patients are at risk of developing new sites of clinical spinal cord compression. And finally, further efforts to better identify patients at high risk of radiographic and clinical spinal cord compression are warranted to refine selection of groups for screening spinal MRI. Thank you very much for your attention, and we hope you enjoyed this UroToday Journal Club discussion of the recently published PROMPTS trial.