First Head-to-Head of Chemo for Prostate Cancer

Pam Harrison

August 09, 2017

The first head-to-head comparison of two taxanes in metastatic castrate-resistant prostate cancer (mCRPC) found similar survival gains but different toxicity profiles, suggesting treatment might be tailored to individual patient needs.

The phase 3 study, known as FIRSTANA, pitted cabazitaxel (Jevtana, Sanofi-Aventis) against docetaxel (Taxotere, Pfizer) for first-line use.

At present, cabazitaxel is approved for use in mCRPC only after progression following first-line treatment with docetaxel. This study was supported by the manufacturer, Sanofi, and was part of the postmarketing requirement for this drug, the authors note.

"This is the first trial to compare two life-prolonging therapies in this setting, and while we did not show superiority of cabazitaxel compared with docetaxel in terms of overall survival, we did show that cabazitaxel is an effective therapy in the frontline setting for mCRPC, although it's no better than the current standard," senior author Oliver Sartor, MD, Laborde Professor of Cancer Research, Tulane School of Medicine, New Orleans, Louisiana, told Medscape Medical News.

"[But because] toxicities differ, there may be consideration for use of these drugs in the context of very specific settings, and this is probably why this trial will be important 5 and 10 years from now, because we really did the right trial," he added.

The study was published online July 28 in the Journal of Clinical Oncology.

FIRSTANA was designed to see whether cabazitaxel at a dose of either 25 mg/m2 (C25) or 20 mg/m2 (C20) was superior to docetaxel at a dose of 75 mg/m2 (D75) when given as first-line therapy to chemotherapy-naive men with mCRPC. Each arm received the chemotherapy intravenously once every 3 weeks, plus oral prednisone, 10 mg/day. A median of nine treatment cycles were given in each group.

A total of 1168 men with mCRPC were enrolled in the trial: 389 were randomly assigned to the C20 arm; 388 to the C25 arm; and 391 to the D75 arm.

"The majority of patients had received prior anticancer hormonal therapy," the investigators observe; "approximately one third of patients in each group had received three or more regimens," they add.

Details of the Results

The primary end point was overall survival (OS). Secondary end points included multiple measures of efficacy, including progression-free survival (PFS), tumor response, and time to symptomatic skeletal-related events (SREs).

Estimated median OS rates were very similar in each of the three treatment groups, at 24.5 months for men in the C20 arm; 25.2 months for those in the C25 arm, and 24.3 months for those in the D75 arm.

Median PFS rates were also very similar across the three groups, at 4.4, 5.1 and 5.3 months, respectively.

Other secondary efficacy end points were also quite similar across all three treatment groups, as shown in the table below.

Table. Comparison of Secondary End Points Between the Three Treatment Groups

  Median Time to Tumor PFS Time to PSA Progression Median Time to Pain Progression Tumor Response Rate (Complete or Partial) Percentage of Patients With SREs Median Time to SRE-Free Survival
C20 13.4 months 8.2 months 8.0 months 32.4% 36% 19.2 months
C25 13.1 months 9.2 months 7.3 months 41.6% 40.7% 17.1 months
D75 12.1 months 8.3months 10.1 months 30.9% 34% 19.0 months


Different Toxicity Profiles

Rates of grade 3 or 4 treatment-emergent adverse events (TEAEs) were highest for men receiving the higher dose of cabazitaxel, at 60.1%, compared to 41.2% for the lower dose and 46.0% for the docetaxel arm.

However, the types adverse events did differ between the groups. Men receiving cabazitaxel were more likely to experience febrile neutropenia, neutropenic infection, diarrhea, and hematuria than those who received docetaxel.

In contrast, men treated with docetaxel were more likely to experience peripheral neuropathy, stomatitis, peripheral edema, alopecia, and nail disorders than those who received cabazitaxel.

Rates of hematologic toxicities between the C25 and D75 arms were similar.

Between one quarter and one third of men in each of the three arms discontinued treatment as a result of TEAEs, and a few men in each arm died as a result of an adverse event, the investigators note.

"C20 was associated with numerically fewer grade 3 or 4 TEAEs, serious TEAEs and TEAEs leading to permanent treatment discontinuation, suggesting that cabazitaxel may be better tolerated at the lower dose," the researchers comment.

Health-related quality of life, as assessed by the Functional Assessment of Cancer Therapy–Prostate questionnaire, also did not differ significantly between the three groups, with the exception of physical well-being, which was better preserved among men who received the lower dose of cabazitaxel compared to men in the docetaxel arm.

"The different safety profiles of the two taxane chemotherapies, along with similar efficacy, may offer additional flexibility to prescribing physicians with regard to treatment choices for individual patient-specific profiles in men with neuropathy, edema, or other conditions that may be preferentially exacerbated by docetaxel," investigators conclude.

Frontline Taxane Unchanged

Approached for comment, Andrew Armstrong, MD, associate director for genitourinary research in the Duke Cancer Institute, Durham, North Carolina, cautioned that although both OS and PFS were similar between the three treatment arms, the study was not designed as a noninferiority trial, so physicians should not consider cabazitaxel to be noninferior to docetaxel.

"The standard frontline taxane chemotherapy remains every-3-week docetaxel and prednisone, with ongoing androgen deprivation therapy (ADT)," Dr Armstrong told Medscape Medical News in an email.

Nevertheless, the FIRSTANA study was helpful in that it showed that the two taxane regimens did have different toxicity profiles.

"These differences may allow clinicians some flexibility when deciding which frontline taxane to choose for patients with existing comorbidities," Dr Armstrong said.

For example, for a patient with preexisting sensory neuropathy from diabetes or other causes, cabazitaxel may result in similar efficacy as docetaxel, but it is less likely to cause a worsening of neuropathy, he suggested.

"The default dose of cabazitaxel for fit men with mCRPC post docetaxel who wish to be aggressive in their care should remain 25 mg/m2 every 3 weeks with prednisone and ongoing ADT, given the slightly greater efficacy and response rates [seen with the higher dose]," Dr Armstrong noted.

However, for men with mCRPC who have undergone treatment with docetaxel and are more frail or have impaired functional status, starting cabazitaxel at a dose 20 mg/m2 dose may be reasonable, given the lower toxicities observed with the lower dose, he added.

The study was supported by Sanofi. Three coauthors are company employees. Several authors have reported relationships with industry. Dr Sartor consults or advises for Bayer, Bellicum Pharmaceuticals, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca (Inst), Progenics (Inst), Dendreon; research funding from Bayer (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Endocyte (Inst), Innocrin Pharma (Inst), Progenics (Inst) and has received travel, accommodations, or expenses from Bayer, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Tokai Pharmaceuticals, AstraZeneca, and Progenics.

J Clin Oncol. Published online July 28, 2017. Abstract


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