On Thursday, here in San Francisco, Dr. Andrew Armstrong first presented the results of the so-called ARCHES trial of enzalutamide (Xtandi) + standard androgen deprivation therapy (ADT) in the treatment of men with metastatic, “hormone-sensitive” prostate cancer (mHSPC). A detailed media release is also available on the Astellas Pharma web site.
The ARCHES trial was designed to test how well men with mHSPC responded to combination therapy with standard ADT + enzalutamide as opposed to standard ADT + a placebo. For the details of the study design, see the study protocol on ClinicalTrials.gov.
This is the first time that any of the new androgen receptor-focused agents has been studied in a Phase III pivotal trial in men with mHSPC.
Basically, the ARCHES trial was a multinational, double-blind, randomized, Phase III trial in which > 1,000 men with mHSPC were randomized to treatment with either
- Enzalutamide (160 mg/d) + standard ADT or
- A placebo + standard ADT
Treatment continued until disease progression or unacceptable toxicity.
Standard forms of ADT included
- A bilateral orchiectomy
- Treatment with an LHRH agonist like leuprolide acetate (e.g., Lupron or Eligard)
- Treatment with an LHRH antagonist like degarelix (i.e., Firmagon)
The primary endpoint for the study was defined as radiographic progression-free survival rPFS — the time from initial diagnosis to the first objective evidence of radiographic disease progression or death from any cause within 24 weeks from study drug discontinuation, whichever comes first.
There were also a number of well-defined secondary endpoints for the trial, that included time to PSA progression, PSA and radiographic responses, and overall survival (OS).
So here are core trial results:
- The trial enrolled 1,150 patients.
- 574 men were treated with enzalutamide + standard ADT
- 576 men were treated with a placebo + standard ADT
- Average (median) follow-up for all patients was 14.4 months.
- 67 percent of the patients had distant metastasis at initial diagnosis.
- 63 percent of the patients had high-volume disease.
- 18 percent of the patients had already been treated with docetaxel-based chemotherapy.
- Compared to treatment with a placebo + standard ADT, treatment with enzalutamide + standard ADT significantly improved rPFS (hazard ratio [HR] = 0.39).
- Median time to disease progression, based on the primary endpoint was
- 19.4 months for men treated with a placebo + standard ADT
- Not reached for men treated with enzalutamide + standard ADT
- There were also significant improvements in several of the secondary endpoints.
- The study data were insufficiently mature to be reported.
- Grade 3 and grade 4 adverse events were reported in
- 23.6 percent of patients treated with enzalutamide + standard ADT
- 24.7 percent of patients treated with a placebo + standard ADT
- No new or unexpected adverse events were observed.
Armstrong and his colleagues concluded that enzalutamnide + standard ADT “significantly improved rPFS and other efficacy endpoints” as compared to a placebo and standard ADT “in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile” of enzalutamide in previous clinical trials of this drug in men with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-resistant prostate cancer (mCRPC).
On the basis of the data presented yesterday by Armstrong and his colleagues, we can reasonably conclude that regulatory authorities around the world (e.g., the FDA here in the US) will approve enzalutamide in combination with standard ADT for the treatment of men with mHSPC. How soon that might happen is more difficult to predict.
The real question about the future use of this form of combination therapy is going to be whether insurance payers (e.g., national payers in countries like the UK or Medicare in the US) will be willing to cover the cost of this form of combination ADT in the treatment of men with mHSPC. The costs are going to be high by comparison with standard ADT, but on the other hand the apparent survival benefits in terms of time to disease progression appear to be considerable too.
As yet, there are no data available to suggest that any specific subset of patients in this trial might benefit greatly from the combination of enzalutamide + standard ADT, but we understand that Pfizer and Astellas will be looking at the available data to see if that might be the case.
Filed under: Uncategorized | Tagged: ADT, ARCHES, enzalutamide, hormone-sensitive, metastatic, mHSPC, Xtandi |
THE "NEW" PROSTATE CANCER INFOLINK 
Please recall randomized trials of ADT plus docetaxel and of ADT plus abiraterone.
Dear Finn:
The trials of docetaxel and of abiraterone were in men with metastatic CRPC as opposed to non-metastatic CRPC.
Dear Sitemaster,
Correct me if I am wrong.
Your statement stated that the ARCHES trial is the “first time that any of the new androgen receptor-focused agents has been studied in a Phase III pivotal trial in men with mHSPC”.
But the LATITUDE, STAMPEDE and even the GETUG-15 trials were based on treatment of metastatic castration-sensitive prostate cancer with docetaxel and abiraterone.
This is unlike the PREVAIL trial where enzalutamide was used in chemotherapy-naïve metastatic castration-resistant (mCRPC) prostate cancer, as well as the COU-AA-302 trial on abiraterone in the same group of prostate cancer patients.
Hence, shouldn’t the statement be that this is the “first time enzalutamide has been studied in a Phase III pivotal trial in men with mHSPC”, rather than any “new androgen receptor-focused agents”?
Isn’t mHSPC (metastatic hormone-sensitive prostate cancer) the same as “metastatic castrate-sensitive prostate cancer / mCRPC”; meaning that trials have already been conducted for abiraterone in this same group of prostate cancer patients, i.e., in the LATITUDE trial? Hence the justification on treating high metastatic volume early castrate sensitive (hormone sensitive) prostate cancer with docetaxel or abiraterone was based on the CHAARTED, LATITUDE, and STAMPEDE trials respectively?
Now with the ARCHES trial, we do have another alternative namely enzalutamide in this same group of patients.
However, unlike the LATITUDE and CHAARTED trial where benefit was seen only in high-volume, metastatic, castrate-sensitive prostate cancer based on their sub-group analysis (although one can argue conclusions from a sub-group analysis is hypothesis-generating only), a prespecified subgroup analysis from this ARCHES trial showed that rPFS (radiographic progression-free survival), which was the primary end-point of the ARCHES trial, was prolonged for patients in the enzalutamide arm for all subgroups, regardless of age, geographic region, Gleason score, volume of disease, or receipt of prior docetaxel therapy.
Also, should there now be a clear distinction in trial settings between metastatic hormone-naive from metastatic hormone-sensitive prostate cancers? “Hormone-naive” meaning ADT has never been started yet in this group of patients under trial, while “hormone-sensitive” meaning that ADT has previously been started and targeted agents are instituted later on, before castrate-resistance develops?
Dr Rajeentheran Suntheralingam
Malaysia
Dear Dr. Suntheralingam:
If we want to be really specific (which is not unreasonable), what I was implying is that the ARCHES trial is the first trial in which any of the three “super-antiandrogens” (enzalutamide, apalutamide, and now darolutamide too) has been tested in a randomized, double-blind, Phase III trial in men with mHSPC.
The STAMPEDE trials are rather different in that they included men who were newly diagnosed but not all of them had metastatic disease. They also enrolled men with high-risk, node-positive disease. And in any case most of these patients were being treated with docetaxel. And a purist would argue that abiraterone acetate is not a super-antiandrogen but is in a different drug class.
One of the problems that we are currently facing is that the language of advanced prostate cancer is now outdated. The term “castration-resistant is rapidly becoming meaningless because one needs to be able to specify exactly what is implied by this term. The term “hormone-sensitive” is also misleading because the patients aren’t being treated with hormones (unless they are being treated with estrogens). Rather, they are being treated with androgen suppressive agents. And you are correct in your observation that the term “hormone-sensitive” is not the same as “hormone naive” (or perhaps better still, “androgen suppressor naive”).
Do we need to rethink the definitions used to describe specific types of treatment status for men with progressive forms of prostate cancer? Yes, I believe we do. The problem is that this will be as much as “political” problem as a scientific and linguistical one.