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Christopher Wallis: Hello, and thank you for joining us for UroToday Journal Club. Today, we are discussing a recent publication in the Journal of Clinical Oncology, entitled Radiation and Androgen Deprivation Therapy With or Without Docetaxel in the Management of Nonmetastatic Unfavorable-Risk Prostate Cancer, A Prospective Randomized Trial. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto, and with me today is Zach Klaassen, also an Assistant Professor in the Division of Urology, at the Medical College of Georgia. This is the citation from this recent publication led by Dr. D'Amico and published in the Journal of Clinical Oncology.

The role of docetaxel in advanced prostate cancer has evolved over time, and most will know that on the basis of data from TAX 327 this was the first approved agent with demonstrated overall survival benefit for patients with metastatic castration-resistant prostate cancer. And subsequently, it has moved forward in the disease space to be used widely in metastatic castrate-sensitive disease on the basis of data from LATITUDE and from STAMPEDE.

A question, therefore, has been, can we use docetaxel to clinical benefit in patients who do not yet have metastatic disease? And so this has been examined most prominently among patients with unfavorable risk non-metastatic prostate cancer. And this remains an open question and one that is assessed by the present trial.

There are, however, a number of other studies that have been done in patients with non-metastatic prostate cancer, assessing the role of docetaxel in combination with radical prostatectomy or radiotherapy and androgen deprivation. In total, seven RTCs have been performed and six of them reported to date, with this being the final. All six reported RCTs have either been negative or inconclusive. And when we say inconclusive, two studies showed an overall survival benefit without a prostate cancer-specific mortality benefit, which is a surprising outcome for a prostate cancer-directed intervention.

There are two hypotheses that were put forth. The first is that docetaxel may reduce prostate cancer-specific mortality in a specific subset of patients who have AR-independent tumors. Alternatively, it may reduce non-prostate cancer-specific mortality from RT radiation therapy-induced cancers.

So in this [inaudible] study the authors performed an investigator-initiated multicenter phase III randomized controlled trial, enrolling patients with histologically proven prostate adenocarcinoma in at least one of the following features, which they used to classify its unfavorable risk:  Clinical stage T2c to 4, PSA greater than 10, Gleason score 4 plus 3, that's grade group 3 or tertiary pattern 5, Gleason score 3 plus 4 in at least 50% of all biopsy cores positive, PSA velocity of 2 nanograms per milliliter per a year or more, or biopsy or radiologic evidence of seminal vesical invasion. Additionally, patients could not have had prior pelvic radiotherapy, prior radical prostatectomy, long courses of pre-enrollment ADT, or evidence of bony or lymph node disease on CT or MRI.

Patients, once enrolled, were randomized in a one-to-one fashion to 6 months of androgen deprivation within LHRH agonist and anti-androgen plus radiotherapy with or without 10 cycles of docetaxel. The patient's randomization was stratified according to the biopsy Gleason Score and PSA level. Radiation was completed with a daily course of 1.8 Gray for 39 treatments, either 3D conformal radiotherapy or IMRT was used with nodal irradiation performed at the discretion of the treating physician.

Patients were assessed at baseline with demographic characteristics, a detailed co-morbidity assessment using the ACE-27, and prostate cancer indices in a digital rectal examination. Following completion of radiotherapy, patients had a PSA and testosterone performed every 6 months for 5 years, then annually. In the case of PSA failure or biochemical recurrence, they underwent restaging with conventional imaging.

The primary endpoint from this study was overall survival, and they also examined overall or radiation-induced cancer as the composite endpoint, and radiation-induced cancer was defined as second cancer other than prostate, thus within the radiation planning target volume.

Secondary outcomes included prostate cancer-specific mortality, metastasis-free survival, and PSA recurrence-free survival. The study was designed to detect the hazard ratio of 0.48, which would be an improved 5-year overall survival from 84% in the control arm to 92% in the conventional arm. They plan to have a one-sided alpha 0.05 power of 80%. And this would require 350 patients and 53 deaths. They subsequently amended their protocol following the publication of some of the other RCTs in this disease space to require 86 deaths, which with the same sample size and longer follow-up would allow for a one-sided alpha of 0.025 and a beta of 0.1, and allowing a power of 90%.

For pre-specified endpoints in the ITT population, they had performed Kaplan-Meier analyses of survival endpoints and used Cox proportional hazards models to estimate hazard ratios. Where there was evidence of non-proportionality, they used restricted mean survival times. They further estimated the cumulative incidence of prostate cancer-specific mortality, radiation-induced secondary cancers, and all second cancers. For these outcomes, they calculated sub-distribution hazard ratios and used stratified Gray's tests to compare patients in the control and experimental arms.

They further performed an exploratory analysis to test whether the effect of adding docetaxel differed based on PSA subgroups. So they defined subgroups of less than 4, 4 to 20, and greater than 20, and performed an interaction test for heterogeneity while adjusting for age, Gleason Score, T-stage, and the percent of biopsy cores that were positive for cancer.

At this point in time, I'm going to hand it over to Zach to walk us through the results.

Zachary Klaassen: Thanks, Chris. So this is the CONSORT diagram for this trial, where there were 350 patients that were randomly assigned equally to ADT plus radiotherapy on the left-hand side of the figure and ADT plus radiotherapy plus docetaxel on the right-hand side of the figure. You can see that about halfway down the figure, 156 patients completed ADT plus RT, and 155 patients completed ADT plus radiotherapy plus docetaxel. At the bottom, you can see that 45 patients in the ADT plus radiotherapy arm passed away, and 44 died in the allocated to ADT plus radiotherapy plus docetaxel arm.

This is the first of two slides looking at the demographic and treatment characteristics for this trial stratified by ADT plus RT, and ADT plus RT plus docetaxel. You can see that about three-quarters of the patients were white. The majority of patients in the docetaxel arm were T1c at 32% of patients. Whereas, the most common T-stage in the ADT plus radiotherapy arm was T1c and T2c. Going down to the bottom of this slide, the most common biopsy Gleason score was a 4 plus 3 at 30% in the ADT plus radiotherapy arm, and 28% in the ADT plus radiotherapy plus docetaxel arm.

The second half of this table shows that the majority of patients over 90% were an ECOG performance of 0 with minimal to no comorbidities. In looking at the PSA levels, you can see that the majority of patients, about three-quarters, had a PSA less than 20. Looking at age, the median was 66 years for both arms and the percent positive biopsy cores was a median of 58% positive for those in the ADT plus radiotherapy arm, and 62.5% in the docetaxel arm.

This is the Kaplan-Meier curve estimate for overall survival, you can see ADT plus radiotherapy in the blue line, and ADT plus radiotherapy plus docetaxel in the red line. And essentially almost overlapping curves here with a hazard ratio of ADT plus radiotherapy plus docetaxel versus ADT plus radiotherapy of 0.99 and a 95% confidence interval of 0.65 to 1.51.

This is the subgroup analysis for overall survival. You can see at the hazard ratio of 1 and the 95% confidence interval for all of these variables crossing the hazard ratio of 1. So no difference in treatment effect for comorbidity, Gleason score, or testosterone between these groups.

This looks at the cumulative incidence estimate of radiation therapy-induced secondary cancers. Again, the ADT plus radiotherapy arm is in blue, and the docetaxel arm is in red. And you can see that at about 8 years since randomization, there's an uptick in the radiation-induced cancer arm of the ADT plus radiotherapy patients.  And so this led to a hazard ratio of 0.13 and a confidence interval of 0.02 to 0.97. And furthermore, you can see the 10-year cumulative incidence of radiation-induced secondary cancers was only 0.61% in the docetaxel arm and 4.9% in the ADT plus radiotherapy arm.

This figure looks at the cumulative incidence of all other cancers, and essentially no difference between these two arms with a hazard ratio of 0.89 and a confidence interval of 0.50 to 1.60.

This table looks at the treatment effect of adding docetaxel to ADT plus radiotherapy on overall survival. And you can see here, this is the PSA-defined subgroups. So on the left, you can see PSA less than 4, PSA 4 to 20, and PSA greater than 20. This is the overall survival event looking at the ADT plus radiotherapy plus docetaxel arm versus the ADT plus radiotherapy arm with a reference group being the PSA 4 to 20 delineation here.  So essentially, if you look at this table, PSA less than 4, the top line is the unadjusted hazard ratio, and the bottom line is the adjusted hazard ratio. You can see that there is a significant improvement in overall survival for the docetaxel arm for PSA less than 4. You also see this in the PSA greater than 20 arm, compared to the PSA 4 to 20 arm as well.

So looking at the next figure, we can start to tease out why this may be the case, and this has to do with prostate cancer-specific survival. And so I've highlighted prostate cancer cause of death here stratified by the PSA arms. In patients with a PSA less than 4, there was no prostate cancer-specific mortalities among those receiving docetaxel compared to 28% in those just receiving ADT plus radiotherapy. And so this differs from patients that had a PSA of 4 to 20, where there were 10.6% deaths in the docetaxel arm from prostate cancer, compared to 6.9% deaths in the radiotherapy ADT arm. And we can see in the PSA greater than 20 arm, there is a prostate cancer-specific mortality of 20.4% in the docetaxel arm, compared to 17.7% in the ADT arm. So we see here, taking these last two slides together, that the improvement in survival for those with a PSA less than 4 appears to be secondary to the addition of docetaxel.

So several discussion points from this trial, like previous randomized controlled trials, men with unfavorable M0 prostate cancer randomly assigned to receive docetaxel plus ADT plus radiotherapy compared to those receiving ADT plus radiotherapy did not experience improved overall survival. Neoadjuvant/concurrent docetaxel use significantly reduced the incidence of radiotherapy-induced cancers. And this is clinically relevant, as these cancers are typically radiation or chemotherapy-resistant and often fatal.

As we just discussed in the last couple of slides, the treatment effect of adding docetaxel to ADT plus radiotherapy on overall survival differed in men with PSA less than 4 versus those with PSA 4 to 20, because of the decrease in prostate cancer-specific mortality in the docetaxel arm compared to men with PSA less than 4. And this has evidence supporting the presence of distinct biology in low PSA producing unfavorable risk prostate cancer that may be docetaxel sensitive.

So the observation of reduced radiotherapy-induced cancer incidence with docetaxel has not been previously reported until this trial. And this may be explained by the short life expectancy of patients because of the advanced stage of some of these cancers relative to the time to onset of a radiation-therapy induced cancer. Or it may be due to the lack of radiotherapy used in the studies that led to the FDA approval of docetaxel for prostate cancer.

Importantly, as the authors point out, a radical prostatectomy control arm was not available to adjust for the incidence of expected cancers, and thus, the point estimates of radiotherapy-induced cancers could include those expected cancers.

And the final point in the discussion session, the ADT duration was 6 months and not 24 to 36 months, as in previous RCTs. And the observation to adding docetaxel to ADT plus radiotherapy may prolong overall survival in men with PSA less than 4 should not be affected by this difference in ADT duration, given that patients with high-grade disease that have a low PSA often have a short-lived PSA response to ADT, suggesting that they already have inherent ADT resistance.

So in conclusion, adding docetaxel to ADT plus radiotherapy did not prolong overall survival in men with unfavorable-risk prostate cancer. However, docetaxel plus ADT plus radiotherapy decreased the incidence of radiotherapy-induced cancers. And to summarize, docetaxel plus ADT plus radiotherapy may prolong overall survival in the subgroup of men with PSA less than 4 by reducing prostate cancer-specific mortality.

Thank you very much. We hope you enjoyed this UroToday Journal Club discussion.