Patrick G. Pilié, MD, presents data from the phase 3 PROSPER trial of enzalutamide, and Ganesh V Raj, MD, PhD, presents data from the phase 3 ARAMIS trial of darolutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC).
Ganesh V Raj, MD, PhD: With that, I will stop and turn it over to Patrick for the PROSPER trial.
Patrick G. Pilié, MD: Thanks so much. Presenting the PROSPER trial, published in The New England Journal of Medicine in June 2018. There are many similarities to the trial just presented. In this case, it looked at patients with M0 castration-resistant prostate cancer [nonmetastatic CRPC], with PSA [prostate-specific antigen] doubling time of equal to or less than 10 months and randomized 2:1, enzalutamide at 160 mg daily with continued ADT [androgen deprivation therapy] versus placebo. The primary end point was similarly metastasis-free survival [MFS] with the secondary end points again of safety, PSA progression, overall survival, and quality of life.
Similarly, the groups are fairly well matched, with the median PSA doubling time at just under 4 months. The majority of patients in both the placebo group as well as the enzalutamide group had a PSA doubling time of less than 6 months. The trial met its primary end point of improved metastasis-free survival with 22 months longer with enzalutamide vs the placebo group, giving around a 70% relative risk reduction for progression or death. Importantly, the secondary end point of overall survival significantly improved in the patients who received enzalutamide versus placebo.
Adverse events were similar to the adverse events seen when enzalutamide is used in patients with M1 castrate-resistant prostate cancer. Notable fatigue is a main concern. It’s important to point out adverse events are a primary reason for treatment discontinuation, however it was relatively similar between the patients who received enzalutamide or placebo. Now I will hand it over to Dr Raj.
Ganesh V Raj, MD, PhD: The ARAMIS trial follows the same script as the other 2 drugs followed in nonmetastatic CRPC, except this is for darolutamide. Again, 1500 patients with nonmetastatic CRPC were randomized 2:1 to get either darolutamide or placebo with the same end point: metastasis-free survival. Overall survival is the secondary end point. The groups were similarly matched, almost the same age, 74; same PSA doubling time, around 4.5 months, very similar for both groups; similar use of bone-sparing agents, ECOG performance [status], and prior hormonal therapies.
Overall, the end point is virtually the same. The darolutamide treatment for M0 CRPC delayed the onset of metastasis significantly compared to placebo. Placebo is 18 months and darolutamide is 40 months, a 22-month improvement in survival with a hazard ratio of 0.41 and a P value of less than .01. This is a significant increase in metastasis-free survival. One of the key things here is that the median survival in terms of overall survival has not quite yet been reached. The 50% point has not been reached for either placebo or darolutamide, so the hazard ratio is still significant at 0.69 and the curves that diverge with a significant P value at this point of follow-up.
The ARAMIS trial for darolutamide basically also showed a significant [adverse] effect profile compared to placebo, with a slightly increased amount of fatigue compared to placebo. Overall, the risk of falls and the risk of bone fractures were comparable to placebo and not particularly worse.
If you compare the SPARTAN, PROSPER, and ARAMIS trials, there was a similar number of patients enrolled and similar inclusion criteria. All of them had the same 2:1 ratio of drug to placebo. Primary end point in all of them was metastasis-free survival. Secondary end point in all of them included overall survival. Key differences, the darolutamide trial has not yet reached the 50% point for median survival for overall survival. In terms of the MFS, you can see all of them have about a 22 to 24-month improvement in survival: 24 months for apalutamide, 22 months for enzalutamide, and 22 months for darolutamide. Slight differences are only attributed to different patient selection criteria. Overall PFS [progression-free survival] is similar. There’s a significant improvement in overall survival for all of these patients. These 2 trials were presented earlier. They have a longer follow-up, therefore we know more about them than others. In all of them, they were relatively well tolerated.
Transcript edited for clarity.