Today at the ASCO annual meeting, Maha Hussein presented the results a long-term, international, randomized trial of intermittent androgen deprivation (IAD) versus continuous androgen deprivation (CAD) in men with hormone-sensitive, metastatic prostate cancer. The abstract giving the major results of this trial (known as the S9346/INT-0162 trial) were posted on line late last night, but the results of this trial are complex and are going to take people time to think about and digest, so we wanted to hear Dr. Hussain’s full presentation before posting commentary on line.
The trial was initiated some 17 years ago, and was designed to enroll patients with hormone-sensitive, metastatic disease who had a SWOG performance status of 0-2 and whose PSA level was ≥ 5 ng/ml at time of study entry. All patients were initially treated for 7 months with goserelin acetate + bicalutamide.
The primary objective of the study was to assess whether the overall survival (OS) of the men treated with IAD was any worse than the OS of the men treated with CAD. Technically, this is referred to as a “non-inferiority” study, in which the researchers seek to demonstrate that an outcome with an investigational treatment (in this case IAD) is pretty much just as good as the outcomes known to occur with a standard form of therapy (in this case CAD).
After the initial 7 months on treatment, patients who achieved PSA levels ≤4 ng/ml at months 6 and 7 were stratified according to three criteria:
- Whether they had had prior treatment with neoadjuvant androgen deprivation or finasteride
- Their performance status at that point in time
- The extent of their disease (minimal or extensive)
The patients were then randomized to either CAD or IAD.
Here are the core findings of the study:
- A total of 3,040 eligible patients men were initially enrolled between April 1995 and September 1998.
- After the initial 7 months of CAD, 1,535/3,040 (50.5 percent) achieved a PSA level ≤ 4.0 in months 6 and 7.
- The characteristics of these 1.535 patients were
- Average (median) age, 70 years
- 4 percent had a performance status of 2
- 48 percent had “extensive” disease (defined in terms of how many metastases were visible and where they were situated)
- 12 percent had had prior neoadjuvant androgen deprivation of some type
- The 1,535 patients were randomized to CAD (n = 759) or IAD (n = 770) and treated until their deaths.
- Average (median) follow-up was 9.2 years.
- Serious adverse effects (of grade 3 or grade 4) occurred in
- 32.6 percent of men randomized to CAD
- 30.3 percent of men randomized to IAD
- Median overall survival times were
- 3.6 years from study entry for all 3,040 initially eligible patients
- 5.8 years from randomization for the 759 patients randomized to CAD
- 5.1 years from randomization for the 770 patients randomized to IAD
- The 10-year overall survival rates were
- 17 percent from study entry for all 3,040 initially eligible patients
- 29 percent from randomization for the 759 patients randomized to CAD
- 23 percent from randomization for the 770 patients randomized to IAD
- There was statistically meaningful difference between the overall survival of the men randomized to IAD as compared to those randomized to CAD (hazard ratio [HR] = 1.09) indicating that IAD was not non-inferior to CAD in the treatment of these patients.
- Overall survival was not affected by the race of the patients.
- Neither performance status nor the prior use of hormonal therapy appeared to have any impact on overall survival of men on IAD compared to CAD.
- There were, however, distinctions between the survival of the men randomized to IAD as compared to those randomized to CAD based on the extent of their disease at the time of randomization.
- For the men with extensive disease, HR = 0.96, suggesting that IAD is not inferior to CAD in this group of men.
- For the men with minimal disease, HR = 1.23, indicating that IAD is actually inferior to CAD in this group of men.
- Prostate cancer was determined to be the cause of death in
- 59 percent of men treated with CAD
- 64 percent of men treated with IAD
Hussain et al. conclude that, among men with hormone-sensitive prostate cancer that initially respond to CAD:
- IAD was “not proven to be non-inferior” to CAD overall. (In other words, IAD is less effective than CAD in its effects on overall survival.)
- IAD was not non-inferior to CAD in men with extensive disease. (In other words, IAD is no worse that CAD in its effects on overall survival in this subset of men.)
- IAD was statistically inferior to CAD in men with minimal disease, “suggesting that CAD is the preferred treatment in this group.”
The results of this study have already stimulated fierce debate within the oncology community attending ASCO. Dr. Hussain herself has clearly stated — at a special, hour-long follow-up question and answer session after her original presentation — that she was surprised by the results of this trial. In another commentary, to be posted late tonight or early tomorrow morning, The “New” Prostate Cancer InfoLink will discuss the implications and ramifications of this trial and try to give some perspective on its interpretation and applications for patients and their clinicians.