First-line enzalutamide in high-risk, ADT-naive patients (including those with metastatic disease)

According to data to be presented at the upcoming meeting of the American Society of Clinical Oncology (ASCO), enzalutamide monotherapy substantially reduces PSA levels in androgen deprivation therapy (ADT)-naive patients with progressive or high-risk disease (including men with evident metastases).

The data to be presented by Smith et al. are from an open-label, Phase II, clinical trial of enzalutamide monotherapy at a dose of 160 mg/day for 25 weeks in men who had received no prior ADT of any type but who did require some form of androgen deprivation therapy. Eligible patients had to have a life expectancy of at least 1 year, a non-castrate serum testosterone level of ≥ 230 ng/dl, and an ECOG performance status of 0. The primary endpoint of the study was a reduction in the patients’ PSA levels of ≥ 80 percent compared to baseline at week 25 of therapy.

Here are the data provided in the study abstract (although additional data may actually be presented by Smith et al. at ASCO):

  • 67 patients were enrolled in the trial.
    • Average (median) patient age was 73 years.
    • 26/67 patients (39 percent) had evident metastatic disease.
    • 24/67 patients (36 percent had received earlier radical prostatectomies.
    • 16/67 patients (24 percent) had received prior radiation therapy.
  • Serum levels of enzalutamide reached a steady state after ~4 weeks.
  • 62/67 patients (93 percent) met the prespecified 80 percent reduction in PSA levels at 25 weeks.
  • The average (median) reduction in PSA level from baseline was actually –99.6 percent.
  • Other average (mean) changes in metabolic outcomes at week 25 included:
    • An increase in serum testosterone level of +114 percent
    • An increase in serum estrogen level of +72 percent
    • An increase in serum luteinizing hormone (LH) level of +185 percent
    • A decrease in total body bone mineral density (BMD) of –0.24 percent
    • A decrease in lean body mass of –4.15 percent
    • An increase in fat body mass of  +6.85 percent
    • An increase in bone alkaline phoshoatase level of +14.75 percent
    • An increase in total cholesterol level of +4.55 percent
    • An increase in triglyceride level of +6.48 percent
  • The most common treatment-emergent adverse events were all of Grade 1 and included:
    • Gynecomastia in 24/67 patients (36 percent)
    • Fatigue in 23/67 patients (34 percent)
    • Nipple pain in 13/67 patients (19 percent)
    • Hot flashes in 12/67 patients (18 percent).
  • 5/67 patients (7 percent) had serious adverse events, but none of these show evidence of being drug related.

While this study clearly shows that enzalutamide monotherapy can induce a high rate of response in ADT-naive patients (as assessed by the decline in patients’ PSA levels over 25 weeks), and the level of adverse events observed appears to be relatively mild, we will need more information before clinicians can seriously consider enzalutamide therapy as a first-line option among high-risk, ADT-naive patients.

We will also need to know (a) the effects of other forms of therapy (e.g., LHRH agonists, antiandrogens, and drugs like abiraterone acetate) when used as second-line agents after first-line enzalutamide in patients like this and (b) whether the adverse events observed in response to enzalutamide in this brief (6-month) study are cumulative over a longer time-frame.

2 Responses

  1. WOW!

    As a 14th year veteran of triple IADT, who has been on Casodex/bicalutamide (three IADT cycles) or flutamide (current cycle) as the antiandrogen compenent of IADT, I’m most impressed with these results. Thanks for giving us an advance look at this important abstract. I’m excited that this trial involves patients who have not been on ADT before but who are judged suitable for ADT, though with no requirement that they have metastases; in other words, this trial explores enzalutamide for a very large population of patients.

    While this is just a Phase II trial, the results are so pronounced that I’m confident they will stand up in further trials. That response rate of 93%, meeting a criterion of 80% PSA reduction instead of the usual 50% or more, is highly encouraging. The median PSA reduction of virtually 100% is also highly encouraging. It is also notable that the study was conducted in a multi-center, international manner, which, with the obviously great results for the vast majority of patients, suggests the results will be replicated in further studies. I’m curious whether the 7% who did not meet the mark for PSA reduction achieved a partial response. (The abstract does not indicate that.)

    Regarding side effects, the virtual absence of a decrease in bone mineral density at 25 weeks contrasts most favorably with the significant decrease often seen with the LHRH agonist component of ADT. The 114% increase in testosterone, in the unusual context of that profound plunge in PSA, suggests a welcome boost in quality of life, or, at the least, not a decline, as is typical of ADT. While countermeasures usually help a lot, they often are not nearly fully effective.

    Some of the other side effects, especially involving breast tissue (notably all mild — Grade 1), look typical of antiandrogen monotherapy. There are some countermeasures that are often effective for breast side effects. There are also countermeasures, especially resistance and aerobic exercise (with diet also playing an important role), that can help with weight/fat gain and fatigue while on ADT, and I’ll bet they would have reduced the incidence of adverse lipid effects and fatigue. Countermeasures were not used in the protocol, which is understandable as they likely would have confounded the results for side effects.

    The one area where traditional ADT is likely quite superior is cost. That said, I’m envious. I hope follow-on studies are vigorously pursued.

  2. Jim Waldenfels,

    Thank you for the time spent to post. Your perspective lends context to the statistics.

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