The Pattern of Metastatic Spread Impact on Efficacy of Enzalutamide - The ARCHES Study Journal Club - Christopher Wallis & Zachary Klaassen

August 12, 2021

In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen discuss a publication entitled Efficacy of Enzalutamide Plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: a Post Hoc Analyses of the ARCHES trial. The present study relies upon secondary analysis of the ARCHES trial, a multinational randomized controlled trial that enrolled 1,150 men with metastatic hormone-sensitive prostate cancer, including those who'd had prior docetaxel. Unlike many of the other trials in metastatic hormone-sensitive castration-resistant prostate cancer, this trial primarily assessed radiographic progression-free survival, finding a significant benefit to the use of enzalutamide with androgen deprivation compared to placebo with androgen deprivation.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

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

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we're discussing a recent publication entitled Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: a Post Hoc Analyses of the ARCHES trial.

I'm Chris Wallace, a Fellow in Urological Oncology at Vanderbilt, and with me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

You can see here, the citation for this recent publication in The Journal of Urology, led by Dr. Andrew Armstrong.

And as is highlighted here, the metastatic castration-sensitive prostate cancer disease space has moved relatively quickly. As of 2015, we had not yet seen any life-prolonging therapies beyond androgen deprivation. And since that time, we now have Level 1 evidence supporting four treatment approaches, including docetaxel, abiraterone, apalutamide, and enzalutamide, and you can see at the edges of the figure, the trials supporting each of these.

However, despite these trials and new treatment options, it's important to consider that castration-sensitive prostate cancer or hormone-sensitive prostate cancer remains a heterogeneous condition, and there is a significantly different prognosis on the basis of disease characteristics. And so in particular, those who present with de novo disease have a notably worse prognosis than those who present with metachronous disease and particularly, among those who present with low-volume metachronous disease.

And we've seen through ongoing follow-up of the CHAARTED trial that the effect of docetaxel appears to be differential according to disease volume with a greater benefit in those with high-risk disease, whereas this effect has not been seen with androgen-axis targeting agents.

And so the present study relies upon secondary analysis of the ARCHES trial. And to briefly summarize, this is a multinational randomized controlled trial that enrolled 1,150 men with metastatic hormone-sensitive prostate cancer, including those who'd had prior docetaxel. Now, unlike many of the other trials in this disease space, this trial primarily assessed radiographic progression-free survival, finding a significant benefit to the use of enzalutamide with androgen deprivation compared to placebo with androgen deprivation.

And so to again emphasize, this study utilized conventional imaging with a bone scan, CT, and MRI for identification of metastatic disease that required a performance status of zero or one and allowed prior use of docetaxel.

And randomization as highlighted before was to enzalutamide or placebo along with concomitant ADT, and randomization was stratified according to both disease volume as well as prior use of docetaxel.

And the primary outcome is radiographic progression-free survival as assessed by an independent central review, as well as a number of secondary outcomes, including time to PSA progression, time to new anti-cancer therapy, the PSA undetectable rate, objective response rate, time to first SRE, and time to castration resistance.

And so in this post hoc analysis, the authors considered the pattern of metastasis as a primary exposure and looked at four mutually exclusive categories, including a lymph node only disease, bone-only disease, bone and lymph node disease, and visceral disease with or without bone or lymph node involvement.

In terms of efficacy analyses, they included all patients with metastatic disease at enrollment, and safety analyses included all patients who received at least one dose of study medication. And they used Cox proportional hazards models to estimate hazard ratios in 95% confidence intervals, as well as the Kaplan Meier method to estimate median survival. And in terms of safety outcomes, they used just descriptive analyses to characterize these.

And at this point in time, I am now going to hand it over to Zach to walk us through the results of this post hoc analysis of the ARCHES trial.

Zachary Klaassen: Thanks, Chris.

So this looks at the patient distribution by a pattern of metastatic spread among these 1,146 men with metastatic disease identified at enrollment. The most common set of metastatic diseases you can see in gray here is bone metastasis at 45%. This is followed by bone plus lymph node metastasis at 31%, lymph node metastasis only at 13%, and finally, visceral metastasis plus or minus bone or lymph node metastasis at 11%. Looking specifically at the locations of the visceral metastases, lung without liver was 74%, liver without lung was 13%, both lung and liver at 5%, and other sites at 7%.

This table here looks at baseline demographics and disease characteristics by a pattern of metastatic spread. So on the far left, we have the variables of interest. On the first column to the right of that is lymph node metastasis only, broken down by enzalutamide and placebo. Bone metastasis only to the right, bone plus lymph node metastasis, and finally, on the far right, visceral plus or minus bone or lymph node metastasis.

And so looking at the number of patients, you can see here the most common group was bone metastases only at 260 undergoing enzalutamide, 245 undergoing placebo, followed by the second most common group of bone plus lymph node metastases.

Looking at the median age, this ranged from roughly the late 60s to the early 70s.

The most common race in all of these groups was white ranging from the high 70 percentages to the low to mid 80%.

In terms of ECOG performance status of zero, these are all relatively healthy patients with 70% to 80% of the patients being ECOG zero.

In terms of median PSA, looking at the lymph node metastasis only, ranging from 3.3 to 3.9. It was low as well for bone metastasis only at 2.4, 2.7 and then increasing in bone plus lymph node metastases for those with enzalutamide at 17.6 and median PSA at 11.3 for placebo. Also relatively high for the visceral plus or minus bone or lymph metastases at 12.4 for enzalutamide and 9.9 for placebo.

In terms of the number of bone metastases, less than four was the most common for the majority of these groups with several in the visceral metastases being at about one-third greater than or equal to 10.

In terms of the number of visceral metastases, lung without liver, 81% for enzalutamide and 67.2% for placebo.

This Kaplan-Meier curve looks at radiographic progression-free survival in the overall patient population by the metastatic spread. We will see several figures looking like this one, so orange is lymph node metastasis only, gray is bone metastasis only, purple is bone plus lymph node metastases, and finally, green is visceral plus or minus bone or lymph node metastases.

And for this figure, we can see that the median rPFS was not reached for every group except for bone plus lymph node metastases at 22.1 months. And when using lymph node metastases as the reference group, the hazard ratio was higher for all the other three groups, bone metastasis only with a hazard ratio of 1.90, bone plus lymph node metastases was 2.81, and visceral metastases was 3.02.

This Kaplan-Meier curve also looks at rPFS just within the enzalutamide group. I mean, we can see that the median rPFS was not reached in any of these four groups. However, when we look at the hazard ratio for enzalutamide versus placebo plus ADT, not surprisingly, enzalutamide had an improved rPFS for lymph node metastasis only of 0.43, bone metastasis only of 0.33, bone plus lymph node metastases of 0.31, and finally, visceral metastasis was 0.94, but with a non-significant confidence interval of 0.51 to 1.73.

When looking at the placebo group specifically for rPFS, lymph node metastasis only, and visceral metastasis, the median rPFS was not reached.  In bone metastasis only, it was 19 months, and in bone plus lymph node metastases, it was 14 months.

These Kaplan-Meier curves look at rPFS by a pattern of metastatic spread. Looking at just the patients with lymph node metastases, enzalutamide is in blue and placebo is in red, we can see here a hazard ratio of 0.43 and a non-significant 95% confidence interval of 0.16 to 1.20.

On the right, looking at bone metastases, we see early in the wide splitting of the curves. The enzalutamide median rPFS was not reached, and placebo at 19 months with a hazard ratio favoring enzalutamide of 0.33 and a 95% confidence interval of 0.22 to 0.49.

Looking at bone plus lymph node metastases, also a very wide splitting and an early splitting of the curves, this is also favoring enzalutamide with a hazard ratio of 0.31 and a 95% confidence interval of 0.21 to 0.47.

And finally, looking at visceral metastases on the right, a median rPFS was not reached in either group with a non-significant hazard ratio of 0.94.

These plots look at the efficacy of enzalutamide plus ADT versus placebo plus ADT by a pattern of metastatic spread. We can look at rPFS on the left here, and you can see that the overall population, as well as bone metastasis only and bone plus lymph node metastasis, favored enzalutamide.

In the right-hand figure is time to PSA progression, and you can see on this figure that all of these subgroups, as well as the overall population, favored enzalutamide.

Looking at the time to new antineoplastic therapy, this was significant for enzalutamide in the bone metastasis only and the bone plus lymph node metastases groups.

And on the right, looking at the time to first SSE, we see that it was also favoring enzalutamide for the overall population, as well as the bone plus lymph node metastases subgroups.

And finally, looking at the time to castration resistance, all of these subgroups and the overall population are favoring enzalutamide with a hazard ratio ranging from 0.24 to 0.49.

These figures look at PSA's undetectable rate by a pattern of metastatic spread with enzalutamide in blue and placebo in red. And for all of these groups, you can see that more patients in the enzalutamide cohort had an undetectable PSA rate, as you can see in the figure.

These results are also shown for objective response rate. Once again, enzalutamide is in blue and placebo is in red. And we can see that again, there are more enzalutamide patients, but the differential between the two groups is not quite as strong as for the undetectable PSA rate.

So several discussion points from this post hoc analysis of the ARCHES trial.

Enzalutamide plus ADT provided improvements in rPFS versus placebo plus ADT in men with metastatic hormone-sensitive prostate cancer who had bone metastases only and bone plus lymph node metastases.

Also, we saw that there was an improvement in the time to PSA progression, time to new antineoplastic therapy, time to first SSE, and time to castration resistance.

The lack of a clear benefit for potent AR inhibition with ADT in men with metastatic hormone-sensitive prostate cancer or visceral metastases is similar to those reported with apalutamide in the TITAN trial, as well as enzalutamide in the ENZAMET trial.

And thus, docetaxel may be considered as an initial chemohormonal therapy in patients with visceral metastases.

So in conclusion, this post hoc analysis in men with metastatic hormone-sensitive prostate cancer from the ARCHES study indicated that potent AR inhibition with enzalutamide plus ADT is beneficial in inducing a durable remission, delayed progression, and symptomatic worsening of disease in men with bone and/or lymph node metastases. However, it may be less effective in men with visceral patterns of disease.

And finally, the analyses of mature overall survival data from ARCHES and other trials will augment our understanding of the impact of the pattern of metastatic spread on the treatment of men with metastatic hormone-sensitive prostate cancer.

Thank you very much, and we hope you enjoyed this Journal Club today for UroToday discussing the ARCHES post hoc analyses.
email news signup