Optimal Treatment for Poor Prognosis Metastatic Castration-Resistant Prostate Cancer, Cabazitaxel vs Abi/Enza, Journal Club – Christopher Wallis & Zachary Klaassen

October 6, 2022

Christopher Wallis and Zachary Klaassen discuss the Annals of Oncology article titled “Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2 trial.” The goal of this publication was to determine the optimal treatment for poor prognosis metastatic castration-resistant prostate cancer (mCRPC) patients. This trial recruited patients with ARPI-naïve mCRPC and poor prognosis features including the presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria. 


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

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today we are discussing our recently published trial in Annals of Oncology entitled cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: A multicenter, randomized, open-label phase 2 trial. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt, and 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 recently published and in press article led by Dr. Kim Chi and the group out of Vancouver.

Advanced prostate cancer, as most will know, is a common cause of oncologic death in older men, and prior to death, nearly all patients develop castration-resistant disease. Over the last 15 years or so, we've seen a rapid proliferation of therapy for men with metastatic castration-resistant prostate cancer. This began in 2004 with the publication of the TAX 327 data and approval of docetaxel as the first life-prolonging therapy. Since that time we've seen other cytotoxic chemotherapies, immunotherapy, both with sipuleucel-T as well as pembrolizumab. We've seen androgen axis targeting agents, including abiraterone, and enzalutamide, as well as other agents, including radium-223 as an alpha emitter, and the PARP inhibitors rucaparib and olaparib.

However, treatment choices now become complicated given a large number of treatment options. The CARD trial sought to assess this to some degree, and they included patients with metastatic castration-resistant prostate cancer who have progressed on both prior docetaxel and prior androgen axis inhibition. These patients were randomized to cabazitaxel or an androgen axis inhibitor switch. As you can see in the figure in the lower right, imaging-based progression-free survival, and overall survival were improved for patients who had cabazitaxel rather than a switch to a second androgen axis targeting inhibitor.

In metastatic castration-resistant prostate cancer, there are a strata of disease prognosis, and a number of clinical factors may be used to define these subsets. Patients with poor prognosis have visceral metastasis, rapid progression on ADT, poor performance status, elevated serum LDH and elevated serum ALP. This is based on numerous studies which show relatively consistent results in these groups.

So the objective of this present study was to compare cabazitaxel chemotherapy or advanced androgen axis inhibition, with either abiraterone or enzalutamide, among patients with poor prognosis mCRPC who have not previously received androgen axis inhibitors. This clearly differs from the CARD trial in which, first, the poor prognostic criteria were not required, and secondly, patients had already received androgen axis inhibitors. It is notable that docetaxel was allowed but not required in this present study.

So the authors included patients with a histologic diagnosis of prostate cancer who had metastatic disease based on a CT or bone scan and castration-resistant prostate cancer defined based on the Prostate Cancer Working Group 2 definition. Patients were required to have a poor prognosis on the basis of one of the following features; either liver metastasis, development of CRPC within 12 months of castration, or at least four of the following characteristics and LDH greater than the upper limit of normal; ECOG performance status of 2, visceral metastases, albumin less than 4, and ALP greater than the upper limit of normal, or less than 36 months from the start of initial ADT exposure to castration resistance and study inclusion.

The authors performed this randomized open-label phase II trial in Canada and Australia. They randomized patients in a one-to-one fashion to cabazitaxel plus prednisone or investigator choice of androgen receptor targeting agent enzalutamide or abiraterone. Cabazitaxel was administered as 25 milligrams per meter squared IV every three weeks along with prednisone. Enzalutamide and abiraterone were given in their standard clinical doses. Treatment was continued until progression, toxicity, and withdrawal of consent.

The primary outcome was the clinical benefit rate. This was defined as the PSA decline greater than 50% from baseline, a measurable radiographic response, or stable disease for more than 12 weeks. Secondary endpoints included the duration of therapy, time to PSA progression, time to any progression, progression-free survival, overall survival, safety and toxicity, the proportion of patients who are eligible to cross over to second-line therapy, and the proportion of patients who actually received second-line therapy.

Further exploratory endpoints included assessment among patients who were able to receive the second line of therapy. These included a clinical benefit rate, again in this group, time to PSA progression, time to any progression, progression-free survival, overall survival from the crossover, and additionally, exploratory analyses were undertaken to examine cell-free DNA biomarkers of response.

The assessment was performed with laboratory investigations every three weeks, including PSA, complete blood cell count, and biochemical analysis.  A bone scan and CT scan were performed at baseline and day one of each three-week cycle. The authors collected correlative samples at baseline and again at day one of each three-week cycle. Adverse events were assessed continuously throughout treatment and cell-free DNA was collected at baseline, the end of cycle four, and the end of treatment.

To detect an absolute difference of 20% in clinical benefit with an 80% power and a two-sided alpha of 0.1, the authors determined that a total of 112 patients and 56 patients per arm were required. They undertook their primary analysis via the intention-to-treat principle, and clinical benefit was compared using multivariate logistic regression, including docetaxel therapy prior to index as a covariate. The safety population included all patients who received at least one dose, and exploratory analyses of cell-free DNA were examined using targeted sequencing of an established 73-gene assay.

At this point in time, I will hand it over to Dr. Klaassen to take us through the results.

Zachary Klaassen: Thanks, Chris. So this is a pretty detailed trial profile of this trial. There were 95 patients enrolled, and I will take you through the left side first, which is group A looking at cabazitaxel, of which 45 patients were included. Ultimately 38 patients discontinued cabazitaxel and 25 were started on second-line treatment with either abiraterone, 9 patients, or enzalutamide, 16 patients. Subsequently, 21 patients out of these 25 discontinued their second-line treatment. On the right is group B, which is 50 patients starting with either abiraterone, 27 patients, or enzalutamide, 23 patients, of which 41 discontinued treatment, and 30 started second-line treatment with cabazitaxel. Among these 30 patients, 28 ultimately discontinued their second-line therapy.

These are the baseline characteristics of this trial. On the right is group B. On the left is group A. You can see here that the majority of patients were in their late 60s. Interestingly, looking at median PSA, group B, the enzalutamide or abiraterone group median PSA was 39.4 compared to 18.7 in the cabazitaxel arm. Other points of interest on this slide, despite the poor prognosis, the majority of these patients were either ECOG performance 0 to 1, 91% in group A and 96% in group B. In terms of castration resistance within 12 months of ADT start, 91% of the patients receiving cabazitaxel and 84% of patients receiving either enzalutamide or abiraterone. Looking at prior docetaxel for metastatic castrate-sensitive prostate cancer, 29% for cabazitaxel and 24% for enzalutamide or abiraterone, and prior docetaxel for metastatic CRPC, 27% for cabazitaxel and 28% for enzalutamide or abiraterone.

Looking at the delineation of metastases, most of these patients did have bone metastasis, 80% for the cabazitaxel group and 88% for the enzalutamide/abiraterone group, lung metastases, 24% for each group, liver metastases, more in the abiraterone/enzalutamide group at 24% compared to 11% of those receiving cabazitaxel. Among patients that had at least four of six poor prognostic features, slightly higher in the abiraterone/enzalutamide arm at 36% compared to 29% for cabazitaxel.

This is the clinical benefit of first-line therapy, and as Chris mentioned, the clinical benefit rate is at the bottom. Walking through each of these components, PSA response greater than 50% was 57% in group A, cabazitaxel, and 54% for those receiving either abiraterone or enzalutamide. Looking at the radiographic response, essentially the same between these groups, 22% for cabazitaxel and 21% for abiraterone or enzalutamide. Looking at stable disease greater than 12 weeks, which certainly favored the cabazitaxel arm at 75% compared to 56% for abiraterone or enzalutamide. Taken together, there was a statistically significant improved clinical benefit rate favoring cabazitaxel at 80% versus 62% for abiraterone or enzalutamide.

This is the waterfall plot looking at the best confirmed PSA response to first-line therapy. As mentioned in the previous slide, this was 57% for cabazitaxel and 54% for abiraterone or enzalutamide. This Kaplan-Meier curve looks at the treatment duration for first-line therapy. There was no difference in treatment duration between these two groups, with cabazitaxel median 6.6 months compared to 5.5 months for either abiraterone or enzalutamide. Looking at the Kaplan-Meier curve for overall survival first-line therapy, this was 37 months for the cabazitaxel group and 15.5 months for the abiraterone/enzalutamide group. Although not a significant benefit, the hazard ratio of 0.58 and 95% confidence interval of 0.32 to 1.05 signals that there is a trend towards a benefit for cabazitaxel first amongst these patients.

This is a Kaplan-Meier curve looking at plasma ctDNA fraction and the impact of overall survival. This is an interesting analysis. You can see here in the gray line, this is patients with ctDNA fraction of 0% to 15% who had an overall survival of 38.7 months compared to those with more ctDNA, the red line, at 15% to 100%, with a significant hazard ratio of 3.71 and 95% confidence interval of 1.98 to 6.95. So certainly here seeing that a lower ctDNA fraction has a significant survival benefit with a wide split in the Kaplan-Meier curve here.

This is another Kaplan-Meier curve looking at the time to progression of first-line therapy in four groups of patients. I'll walk you through this curve as there are lots of lines here. You can see here on the left, the light purple line is cabazitaxel with no androgen receptor amplification. The blue line is cabazitaxel with androgen receptor amplification. The light pink line is abiraterone or enzalutamide with no androgen receptor amplification, and the red line is abiraterone or enzalutamide with androgen receptor amplification. Just looking at this on a global scale, you can see here the two light shaded lines, the light pink and the light purple, this is a survival benefit amongst patients either receiving cabazitaxel or abiraterone/enzalutamide that did not have androgen receptor amplification.

Finally, this is overall survival in patients with and without a detectable AR amplification in baseline plasma ctDNA. And again, we can see here in the gray line, this is patients with no detected AR amplification with the median overall survival of 38.7 months, compared to the red line, which is androgen receptor amplification, the median survival of 13.7 months, which was clinically and statistically significant.

So several discussion points from this trial. This is the first trial to randomize androgen receptor pathway inhibitor-naive advanced prostate cancer men to either taxane chemotherapy or androgen receptor pathway inhibitors. It's been previously shown that patients with poor prognostic features do not receive the same level of benefit from androgen receptor pathway inhibitors. The observed higher clinical benefit for the first-line cabazitaxel in this trial was primarily due to more patients in this arm having the stable disease at 12 weeks, and as Chris mentioned, the CARD trial was published a couple of years ago, which showed an overall survival advantage of cabazitaxel versus androgen receptor pathway inhibitors. However, this population had already received both docetaxel and an androgen receptor pathway inhibitor. Thus, the evaluation of cabazitaxel versus androgen receptor pathway inhibitor as third-line therapy in those already resistant androgen receptor pathway inhibitors is different from the clinical trial design of this trial in that these were androgen receptor pathway, inhibitor-naive patients.

This trial also had some interesting findings with regards to ctDNA, and certainly, they showed that ctDNA abundance is emerging as a clinical prognostic marker across disease states and different cancer types. The high average baseline ctDNA fraction in this study was clearly consistent with poor prognostic clinical features and baseline ctDNA fraction was more predictive of outcomes than all routine clinical variables combined in this trial.

So in conclusion, in a poor prognosis mCRPC population, cabazitaxel was associated with a modestly higher clinical benefit rate compared to androgen receptor pathway inhibitors. However, both these treatments should remain important options for patients with androgen receptor pathway inhibitor-naive poor prognosis mCRPC men. Finally, ctDNA abundance was prognostically independent of clinical features and holds promise as a stratification biomarker.

Thank you very much. We hope you enjoyed this UroToday journal club.