Data from a Phase II trial of ARN-509 (apalutamide) and more

A report posted on line in European Urology has provided us with important clinical data related to the potential of this investigational drug in the treatment of advanced prostate cancer.

These data are the first report from relatively small, non-randomized, multi-center, Phase II trial of apalutamide (formerly known as ARN-509) in the treatment of men with non-metastatic, castration-resistant prostate cancer (nmCRPC).

Apalutamide is described by the research team as

a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets.

The patients enrolled in this trial were all meant to be nmCRPC patients with a high risk for progression, i.e., a PSA level ≥ 8 ng/ml or a PSA doubling time of ≤ 10 months. All patients were maintained on androgen deprivation therapy (ADT) and treated, in addition, with apaglutamide at a dose of 240 mg/day. The primary study endpoint was the patients’ PSA response after 12 weeks on therapy. Of the 51 patients enrolled into the trial, it appears that four actually were later found to have had metastatic disease at enrollment, so only 47 of the patients were actually eligible for evaluation with regard to the primary study endpoint.

Here are the key study findings:

  • Patient characteristics included the following:
    • Average (median) age, 71 years
    • 76 percent  had an Eastern Cooperative Oncology Group (ECOG) performance status of 0
    • 57 percent of patients had a Gleason score of 7
    • Average (median) PSA level was 10.7 ng/ml
    • 45 percent of patients had a PSA doubling time of  ≤10 months
  • At the initial 12-week follow-up period, 89 percent of the 47 patients who were actually nmCRPC had a PSA decline of ≥ 50 percent.
  • At an average (median) follow-up of 28.0 months,
    • 18/51 patients (35 percent) were still on study.
    • Average (median) time to PSA progression was 24.0 months.
    • Average (median) time of metastasis-free survival was not reached.
    • 33/51 patients (65 percent) discontinued study treatment.
      • 11/51 patients (22 percent) discontinued due to disease progression.
      • 9/51 patients (18 percent) discontinued because of adverse events.
  • The most common adverse event was fatigue (of any grade) in 31/51 patients (61 percent).
  • Fatigue of  grade 3 or higher was observed in only 2 patients (4 percent).

The authors conclude that:

In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control.

It is clear from these data that apalutamide has activity in the treatment of men with nmCRPC. This is not a surprise. However, the degree of promise for apalutamide based on these data (compared to other drugs already available on the market) is much harder to evaluate. Would treatment of this set of patients with either enzalutamide or abiraterone acetate have shown similar outcomes? We really don’t know.

The ongoing, randomized, multi-center Phase III clinical trial of apalutamide in men with nmCRPC will obviously help us to answer this question. The estimated completion date for this trial is December this year, with a primary endpoint of progression-free survival, but apalutamide is only being compared to a placebo in this trial.

Another ongoing, randomized, multi-center Phase III trial is evaluating standard androgen deprivation therapy (ADT, with an LHRH agonist or surgical orchiectomy) + apaluamide in treatment of men with metastatic hormone-sensitive prostate cancer (compared to standard ADT alone). The estimated completion date for this trial is May 2020, with a primary endpoint of radiographic progression-free survival (rPFS).

A third randomized, multi-center Phase III trial (the ATLAS trial) is evaluating apalutamide even earlier in treatment. In this trial, men with high-risk, localized or locally advanced prostate cancer who are all scheduled for treatment with primary radiation therapy and an LHRH agonist are being randomized to either a standard antiandrogen (bicalutamide) or to apaglutamide as the investigational treatment. The primary endpoint of this trial will be metastasis-free survival, and it may be many years before we see the results of this trial. The projected completion date for this study is December 2022.

A fourth and final randomized, multi-center Phase III trial is evaluating the use of abiraterone acetate + prednisone + apalutamide (as compared to abiraterone acetate + prednisone + a placebo) in treatment of men with chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC). The primary endpoint for this trial is, once again, rPFS, and the estimated study completion date is December 2018.

The developer has clearly invested heavily in the development of apalutamide, and the “New” Prostate Cancer InfoLink remains optimistic that apalutamide will prove to be another valuable addition to the arsenal of drugs available for the treatment of high-risk and progressive forms of prostate cancer. Hopefully we will get a clear signal sometime early in 2017.

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