The treatment of mCRPC with a combination of docetaxel + enzalutamide

We know that both abiraterone acetate (Zytiga) and enzalutamide (Xtandi) can be used to extend the survival of men with mCRPC who have already been treated with docetaxel + prednisone. However, … one of the as yet unanswered questions is whether using drug combinations like docetaxel + abiraterone acetate or docetaxel + enzalutamide can have a substantial impact on the overall survival of patients newly diagnosed with metastatic, castration-resistant prostate cancer (mCRPC) — i.e., an effect greater than either agent alone.

There are several trials that are exploring this question, but one of the earliest reported so far was the data from the CHEIRON trialreported by Caffo et al. at the recent Genitourinary Cancers Symposium in San Francisco. A report on this presentation also appears on the UroToday web site.

The CHEIRON trial enrolled men with mCRPC and randomized them to treatment with

  • Either docetaxel (at a dose of 75 mg/m2 IV) q3w, starting on Day 1, + prednisone (at a dose of 5 mg PO b.i.d) for 8 courses (Group A)
  • Or the same doses of docetaxel + prednisone with the addition of enzalutamide (at a dose of 160 mg PO daily) for 24 weeks (Group B)

All patients in each arm of the trial were also continued on treatment with standard forms of androgen deprivation therapy (ADT)

Since both docetaxel and enzalutamide have been shown to have significant activity when used individually in the treatment of mCRPC, the hypothesis was that one might be able to see greater benefit by giving these drugs in combination.

The primary endpoint for the CHEIRON trial was the proportion of patients with no sign of disease progression (according to Prostate Cancer Working Group 2 criteria) at 6 months after randomization.

Here are the core results of the trial as reported by Caffo et al.:

  • The trial enrolled patients between September 2014 and October 2017.
  • The average (median) age of the patients was 70 years (range, 44 to 88 years)
  • Patients were stratified based on the presence of
    • Bone pain (reported by 54 patients)
    • Visceral metastases (reported by 50 patients)
  • A total of 246 patients were enrolled.
    • 120/246 patients were randomized to treatment in Group B.
    • 126/246 patients were randomized to treatment in Group A.
  • The rates of progression-free survival at 6 months were
    • 87.3 percent in Group B
    • 72.6 percent in Group A
    • This difference was statistically significant (p = 0.006)
  • The percentages of patients showing a decrease in their PSA levels of ≥ 50 percent compared to the baseline values at 6 months were
    • 92.2 percent in Group B
    • 70.0 percent in Group A
    • This difference was again statistically significant (p = 0.0001)
  • There we no differences observed in overall response rates (ORR) at 6 months.
  • At an average (median) follow-up of 20 months, median progression free survival was
    • 11.3 months for men in Group B
    • 9.1 months for men in Group A
    • Again, this difference was statistically significant (p = 0.004).
  • The median overall survival was
    • 30.5 months for men in Group B
    • 28.7 months for men in Group A
    • This difference was not statistically significant
  • Major hematological toxicities included
    • Grade 3-4 anemia (in 3 patients in Group B and 1 patient in Group A)
    • Grade 3-4 neutropenia (in 23 patients in Group B and 19 patients in Group A)
    • Febrile neutropenia (in 10 patients in Group B and 5 patient in Group A).

Cappo et al. concluded that, in this Phase II trial of the treatment of men with mCRPC with docxetaxel + prednisaone compared to docetaxel + prednisone + enzalutamide, the addition of the enzalutimde improved the 6-month progression-free survival compared to the standard chemotherapy. However, it should be noted that toxicities were generally higher among the patients in Group B, and the most common of these toxicities was fatigue (in 12.5 percent of the patients in Group B).

While the results of this Phase II pilot trial are positive in terms of the impact on progression-free survival at both 6 and 20 months from randomization, it has to be noted that the impact on overall patient survival was limited, and not statistically significant. The adverse effects of treatment also seem to be generally greater in the docetaxel + enzalutamide combination arm.

At present we see no signs of any Phase III trial that is exploring the potential of drug combinations of this type in the first-line treatment of mCRPC.

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