This was a huge trial with 1,068 patients treated at 256 centers around the world. To qualify, patients had to have:
- Biochemical progression after attempted curative treatment with prostatectomy (RP), radiation (RT), or both (SRT).
- PSA≥ 1 ng/ml if RP; ≥ 2 ng/ml above nadir if RT
- PSA doubling time (PSADT) ≤ 9 months
- No metastases on conventional imaging
Patients were randomized to one of three groups:
- enzalutamide + ADT with leuprolide (combination)
- ADT (leuprolide)-only (the control group)
- enzalutamide-only (enza monotherapy)
The control group received a placebo (blinded). The third group was not blinded. There were periodic PSA tests, but neither patients nor their physicians were privy to the PSA results.
One of the goals of the trial was to see which treatment strategy allowed for the longest hormone-therapy vacation (see this article about intermittent ADT- Setting 3). Patients in all 3 groups were given a hormone therapy vacation as long as their PSA became undetectable (< 0.2) by week 36. The vacation ended when PSA rose to ≥ 2.0 (if previous RP) or ≥ 5.0 (if no previous RP).
After 5 years of follow-up, the early results were reported by Neal Shore at an ASCO meeting:
- Relative to the control group, the incidence of distant metastases was reduced by 58% by combination therapy, and by 47% by enza monotherapy.
- Overall survival results are not yet mature, but so far mortality has been reduced by 41% by combination therapy, and by 23% by enza monotherapy
- Time to PSA progression (castration resistance) was increased by 93% by combination therapy, and by 67% by enza monotherapy.
- Time to chemotherapy was increased by 64% by combination therapy, and by 46% by enza monotherapy.
Vacation (iADT) Results
- The percentage of patients that achieved undetectable PSA (< 0.2) by week 36 of therapy and were able to take a vacation was 91% for the combo, 68% for the control, and 86% for enza-monotherapy.
- The vacation lasted for 20 months for the combo, 17 months for the control, and 11 months for enza-monotherapy
- Testosterone only reached about half of baseline during the vacation in the combination and control groups. Testosterone rose to well above baseline in the enza-monotherapy group.
- Serious or worse adverse events attributable to medications occurred more often in the groups given enzalutamide (18% of the combo and 16% of the enza monotherapy groups compared to 9% in the leuprolide-only group).
- Fatigue was the most common side effect and occurred more often with enzalutamide (47% for the monotherapy, 43% for the combination) than with leuprolide alone (33%)
- Hot flashes much less often occurred in the enza-monotherapy group (22%) than in the combination group (69%) or the leuprolide-only group (57%).
- Gynecomastia/nipple pain was prevalent in the enza-monotherapy group (45%/15%)
- All other side effects were experienced about equally.
- If one is recurrent with PSADT≤ 9 months, treatment with a combination of Lupron and Xtandi improves oncological outcomes
- If the trial were started now, everyone would get a PSMA PET/CT. It is likely that most would detect distant metastases.
- Intermittent hormone therapy is likely to provide the longest vacation if one is getting the combination, but the quality of the (half as long) vacation may be better with enza-monotherapy because of greater testosterone recovery.
- Enzalutamide increases many side effects, including fatigue.
- Enza-monotherapy is less likely to cause hot flashes, but more likely to cause gynecomastia.