2. UroToday Home
  3. Transformative Evidence
  4. The ARAMIS Trial: Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer
  5. Articles
  6. Conferences
  7. ASCO GU 2019
  8. ASCO GU 2019

ASCO GU 2019: Discussion on: The ARAMIS Trial, the Final Analysis of LATITUDE Study, and the ARCHES Trial

San Francisco, CA (UroToday.com) Dr. Ian Davis provided a discussion of the 3 positive clinical trials just presented – LATITUDE (final results), ARAMIS, and ARCHES. He did start by noting his conflicts of interest, particularly that he is an advisor for many of the companies – but also, that as an Australian, he is a believer in affordable universal health care (and cost-effective healthcare delivery).

When he addresses each of the trials, he asks the following question to determine if it should change clinical practice:
  • 1) Is the condition one that requires treatment?
  • 2) Is there a meaningful endpoint?
  • 3) Does the agent have acceptable toxicity?
  • 4) Does it compromise the efficacy of subsequent therapies?
  • 5) Ideally, it must also be cost-effective
ARAMIS
  1. Is the condition one that requires treatment?
M0 CRPC is a nebulous disease space. It is essential patients with cM1 disease for whom metastatic lesions can’t be identified by conventional imaging. However, as imaging becomes more sensitive, the cM0 disease will continue to shrink.
  • But, data by Smith et al. (JCO 2013), did demonstrate that men with cM0 PCa and PSADT <=6 months had significantly worse outcomes than men with PSA DT > 6 months
  • So, men with cM0 PCa with PSA DT <= 6 months likely still warrant treatment.
As ARAMIS was predominantly made up of men with PSADT <= 6 months, this is a disease process that warrants treatment.

  1. Meaningful endpoint? The primary endpoint was MFS, which it met. However, there is debate as to whether this translated to OS benefit. It was sufficient enough for the FDA to approve it based on MFS survival benefit alone. - Possible meaningful benefit
  1. It does have acceptable toxcicity
  1. It is uncertain whether or not it affects subsequent therapy effectiveness. No data for analysis.
  1. Cost-effectiveness – Unfortunately, as there is no price yet or OS data yet for darolutamide, there is no way to calculate ICER or cost-effectiveness.
At this point, on what we know so far, it is unclear if this should change practice. More data is required.

LATITUDE
  1. Is the condition one that requires treatment?
Yes. These patients have metastatic disease and warrant additional treatment.
  1. Meaningful endpoint? In this final analysis, they provide updated OS data. This is a meaningful endpoint. Compared to the interim results previously provided, the OS data has matured, but remains very significant. There is a 36% risk reduction (HR 0.66, p < 0.0001).
  1. Toxicity – In their QOL and safety analysis, they note that patients on abiraterone vs. placebo have much higher QOL scores throughout the course of the study. The adverse event profile was also appropriate for abiraterone.
  1. Does it affect subsequent treatment?
LATITUDE introduced a novel endpoint called PFS2, which the time to progression on the next life-extending therapy. In LATITUDE, the use of abiraterone first line actually resulted in extended PFS2 – meaning that patients who were treated with abiraterone + ADT up front responded better to second line therapy as well. This suggests that it results in delay in need and reduced need for secondary therapies.

  1. Cost-effectiveness: This is the only criteria that it perhaps does not meet. The cost of abiraterone is ~$10K/month. As mentioned earlier in the day by Ronald Chen, the incremental benefit of abiraterone in the United States exceeds the $100K/QALY for cost-effective therapy – but if does become generic, it may be considered cost-effective.
- In the UK, current ICER levels are 28-32,000 pounds/QALY
- In Australia, it is approved but not reimbursed

In the United States, the patent overturned in October 2018. The company has appealed in Jan 2019.  In Europe, the exclusivity contract runs through 2022. So, it may be a while before it becomes generic and cost-effective. In conclusion, he notes that it SHOULD change practice, but only IF available and affordable.  Based on subgroup analysis, the greatest benefit may be for low-volume disease – because for high-volume disease, docetaxel may be more cost-effective.

ARCHES
  1. Is the condition one that requires treatment?
Yes. These patients have metastatic disease and warrant additional treatment.
  1. Meaningful endpoint? At this time, the primary endpoint in this first analysis is recurrence progression-free survival (rPFS), though early overall survival (OS) data was also reported.
- He notes that rPFS data may shift as this is only an interim analysis
- The OS data is immature, so an early signal may not be reflective of final results

However, rPFS was significantly improved with enzalutamide use. This benefit extended across subgroups, including low/high volume disease and in patients with prior docetaxel use.

In the following chart, he compares the trials in this disease space:
UroToday ASCOGU2019 ARAMIS ARCHES Discussion

So, it is a questionable endpoint but may become reliable with more mature data.
  1. Toxicity – acceptable toxicity levels. Grade 3/4 AE were as expected. Mean Fact-P scores were no differences between treatment and placebo arms.
  1. Does it affect subsequent treatment efficacy?
Unfortunately, PFS2 was not an endpoint in this study. So, it is unclear if this affects second-line therapy effectiveness.
  1. Is it cost-effective?
There is no good cost-effectiveness data yet. At this time, it is not cost-effective, as there is no final OS data to calculate cost-effectiveness. Therefore, he concludes that it SHOULD NOT change practice … yet.  He does not that he is running a similar trial called ENZAMET in Australia, in which the primary endpoint is OS. So, this trial in conjunction with ENZAMET data may change the outcome in the near future. 


Presented by: Ian D. Davis, MBBS, Ph.D., FRACP, FAChPM, Monash University Eastern Health Clinical School

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

Further Related Content:
Read: Darolutamide Receives FDA Approval for the Treatment of Non-metastatic Castration-resistant Prostate Cancer