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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


September 14, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201023s019lbl.pdf

On September 14, 2017, the U.S. Food and Drug Administration approved a lower dose of cabazitaxel (20 mg/m2 every 3 weeks) (JEVTANA®, Sanofi-Aventis) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. Cabazitaxel (25 mg/m2 every 3 weeks) was approved for this indication in 2010.

The approval was based on data from a noninferiority, multicenter, randomized, open-label trial (PROSELICA) of 1200 patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen. This trial was conducted as a post-marketing requirement to evaluate a lower dose compared with the approved dose of 25 mg/m2. Patients received either cabazitaxel 25 mg/m2 (n=602) or the 20 mg/m2 (n=598) dose.

The trial demonstrated noninferiority in overall survival (OS) of cabazitaxel 20 mg/m2 in comparison with 25 mg/m2 in an intent-to-treat population. The estimated median OS was 13.4 months for patients on the lower dose compared with 14.5 months for patients receiving the higher dose (hazard ratio=1.024; 97.78% CI: 0.886, 1.184). Based on the per-protocol population, the estimated median OS was 15.1 and 15.9 months on cabazitaxel 20 mg/m2 and cabazitaxel 25 mg/m2, respectively (hazard ratio=1.042; 97.78% CI: 0.886, 1.224).

The major safety findings, myelosuppression, infections and increased toxicity, occurred with greater frequency on the 25 mg/m2 arm compared to the lower dose. Deaths within 30 days of the last study drug dose (5.4% vs. 3.8%), and early infection-related deaths within 30 days of the treatment initiation (1.3% vs 0.7%) were more common on the 25 mg/m2 arm compared to the 20 mg/m2 arm. All of the early infection-related deaths occurred in patients greater than 60 years of age. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.

Adverse reactions and laboratory abnormalities occurring in greater than 10% of patients treated with cabazitaxel on clinical trials were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, and anorexia. Grade 3-4 infections were reported in 20% patients on the 25 mg/m2 arm and 10% patients on the lower dose. Febrile neutropenia occurred in 9% of patients on the 25 mg/m2 arm and in 2% on the 20 mg/m2 arm. The most common reasons for dose discontinuation were fatigue and hematuria.

The recommended dose of cabazitaxel is 20 mg/m2 administered every three weeks as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily. A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider.

The full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201023s019lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

Pharmacist’s Applications to Practice

Cabazitaxel 20 mg/m2 for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Previously Treated with a Docetaxel-Containing Regimen

Author: Sidney V. Keisner, PharmD BCOP BCPS
Hematology/Oncology Clinical Pharmacy Specialist
Central Arkansas Veterans Healthcare System
Little Rock, AR

What is the potential role for cabazitaxel 20 mg/m2 in the management of prostate cancer?

  • The U. S. Food and Drug Administration (FDA) labeling for cabazitaxel (Jevtana) was recently modified: the recommended starting dose was decreased from 25 mg/m2 given intravenously (IV) every 3 weeks to 20 mg/m2 IV every 3 weeks with the option of using the higher dose in selected patients.
  • An FDA-required postmarketing study found that overall survival (OS) with lower-dose cabazitaxel was noninferior as compared with the higher dose. The lower dose was also associated with significantly lower adverse-event rates. These findings led to the labeling changes for cabazitaxel.
  • Cabazitaxel, a taxane microtubule inhibitor, was originally approved by the FDA in June 2010 in combination with prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.
    • Approval was based on the TROPIC trial, which demonstrated superior OS with cabazitaxel 25 mg/m2 plus prednisone compared with mitoxantrone plus prednisone (median 15.1 months vs. 12.7 months). The modest improvement in OS was accompanied by high rates of toxicity. Grade 3 or worse neutropenia was seen in 82% of patients in the cabazitaxel group, and febrile neutropenia was reported in 8% of patients. Additionally, 5% of patients in the cabazitaxel group, compared with 1.9% in the mitoxantrone group, died within 30 days of treatment. In the cabazitaxel group, most of these deaths were attributed to sepsis, renal failure, or cardiac causes.
    • Because of the OS benefit shown in the TROPIC trial, the FDA originally recommended approval of cabazitaxel at a starting dose of 25 mg/m2 IV every 3 weeks in combination with prednisone.1,2
  • The original FDA-approved dose was not finalized without debate. In a phase 1 trial, cabazitaxel had a maximum tolerated dose (MTD) of 20 mg/m2, whereas another trial demonstrated the MTD to be 25 mg/m2. Also, a phase 2 breast cancer trial used a starting dose of 20 mg/m2 with a plan to escalate the dose to 25 mg/m2 as tolerated, and few patients were able to escalate to the higher dose. Despite these indicators that 25 mg/m2 may not be well tolerated, the FDA was compelled to approve the starting dose of 25 mg/m2 because this was the dose associated with improved outcomes in the TROPIC trial. Because of these concerns about toxicity in early trials and the significant toxicity seen in the TROPIC trial, the FDA required a postmarketing study comparing the efficacy and safety of the 25 mg/m2 dose versus the 20 mg/m2 dose in patients with mCRPC.3
    • A phase 3 open-label study (PROSELICA) randomized postdocetaxel patients with mCRPC to either cabazitaxel 20 mg/m2 IV every 3 weeks or cabazitaxel 25 mg/m2 IV every 3 weeks (both arms were given prednisone 10 mg daily), aiming to assess noninferiority of the lower dose. The primary end point was OS, and key secondary end points included progression-free survival (PFS), tumor response, time to tumor progression, prostate-specific antigen (PSA) response, and time to PSA progression. A total of 1,200 patients were enrolled. Median OS in the intention-to-treat population was similar between groups at 13.4 months in the 20 mg/m2 group versus 14.5 months in the 25 mg/m2 group, and noninferiority was established. A significant difference was not seen between groups for PFS, tumor response rate, or time to tumor progression. However, PSA response rate (30% versus 43%) and time to PSA progression (median 5.7 months versus 6.8 months) were statistically worse in the 20 mg/m2 group.4
    • Grade 3 or higher toxicity was observed at a lower rate in the 20 mg/m2 group (40% vs. 55%), including lower rates of febrile neutropenia (2% vs. 9%), neutropenia (42% vs. 73%), and diarrhea (1.4% vs. 4%). Rates of peripheral sensory neuropathy were also lower in the 20 mg/m2 group (all grades: 6.6% vs. 10.6%; grade 3 or worse: 0% in both groups).
    • Fewer dose reductions were required with the lower dose of cabazitaxel (10.2% vs. 21.7%), and incidence of death within 30 days of the last treatment was 2.1% in the 20 mg/m2 group and 3.2% in the 25 mg/m2 group.4

What role can the pharmacist play in the management of patients on cabazitaxel?

The pharmacist can take the following steps:

  • Prospectively review for patient-specific factors to determine the appropriate starting dose for a given patient.
  • Recommend and manage dose modification when indicated.
    • Toxicity
      • For starting dose of 20 mg/m2, decrease to 15 mg/m2.
      • For starting dose of 25 mg/m2, decrease to 20 mg/m2. An additional reduction to 15 mg/m2 may be considered.
    • Renal impairment
      • Use caution if creatinine clearance is less than 15 ml/min or if end-stage renal disease is present.
    • Hepatic impairment
      • Mild impairment (total bilirubin greater than 1 to less than or equal to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) greater than 1.5 times ULN): 20 mg/m2.
      • Moderate impairment (total bilirubin greater than 1.5 to less than or equal to 3 times ULN and any AST): 15 mg/m2.
      • Severe impairment (total bilirubin greater than 3 times ULN): Use is contraindicated.2
  • Recommend and manage appropriate use of granulocyte-colony stimulating factor as primary or secondary prophylaxis.
    • Primary prophylaxis should be considered for high-risk patients including the following: older patients and those with poor performance status, previous febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities.2
  • Assess for drug interactions.
    • Cabazitaxel is a substrate for cytochrome P450 3A4 (CYP3A4). Avoid administration with strong inhibitors of CYP3A4. If concomitant use cannot be avoided, reduce cabazitaxel dose by 25%.2

Clinical Pearls

  • Cabazitaxel 25 mg/m2 should be reserved for fit, healthy patients.5
  • Recommended premedications to reduce incidence of infusion reactions with cabazitaxel include an H1 antagonist, H2 antagonist, and corticosteroid (all given intravenously).2
  • Cabazitaxel is associated with low emetogenic risk. Standard steroid premedication for infusion-reaction prophylaxis is also adequate for nausea and vomiting prophylaxis.6
  • No biomarkers that may predict benefit with cabazitaxel have been identified.5
  • Optimal sequencing of cabazitaxel with other agents indicated for mCRPC (enzalutamide, abiraterone) is unclear at this time.5
  • Sanofi Aventis may provide medication at no cost for patients who meet eligibility requirements.7

References

  1. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  2. Jevtana [package insert]. Bridgewater, NJ: Sanofi Aventis; 2017.
  3. U.S. Food and Drug Administration. Center for Drug Evaluation and Research Application Number 201023 Summary Review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201023s000SumR.pdf. Accessed October 19, 2017.
  4. Eisenberger M, Hardy-Bessard AC, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer—PROSELICA. J Clin Oncol. 2017;35(28):3198-3206.
  5. National Comprehensive Cancer Network. Prostate Cancer Early Detection (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Accessed October 19, 2017.
  6. National Comprehensive Cancer Network. Antiemesis (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed October 19, 2017.
  7. Sanofi Patient Connection. http://www.sanofipatientconnection.com. Accessed October 23, 2017.
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