SIZE XSSIZE SMSIZE MDSIZE LG

The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

You can also find additional information on FDA Alerts and Updates by listening to FDA Drug Safety Podcasts.


April 6, 2018–Rucaparib (Rubraca®, Clovis Oncology Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy (with Pharmacist's Applications to Practice)

December 19, 2016–Rucaparib (RUBRACA™, Clovis Oncology Inc.) granted accelerated approval for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies (with Pharmacist's Applications to Practice)


April 6, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf

On April 6, 2018, the Food and Drug Administration approved rucaparib (Rubraca®, Clovis Oncology Inc.), a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Approval was based on ARIEL3 (NCT01968213), a randomized, double-blind, placebo-controlled trial in 561 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with at least two prior treatments of platinum-based chemotherapy and were in complete or partial response to the most recent platinum-based chemotherapy. Patients were randomized (2:1) to rucaparib 600 mg orally twice daily (n=372) or placebo (n=189) and were treated until disease progression or unacceptable toxicity.

Tumor tissue samples were examined with a next-generation sequencing assay to determine whether DNA contained a deleterious somatic or germline BRCA mutation (tBRCA). This test was also used to determine the percentage of genomic loss of heterozygosity (LOH). Positive homologous recombination deficiency (HRD) status was defined as tBRCA-positive and/or LOH high. Three patient outcomes analyses were performed on the following groups: all patients, HRD subgroup, and tBRCA subgroup.

ARIEL3 demonstrated a statistically significant improvement in estimated median progression-free survival (PFS) assessed by investigator for patients randomized to rucaparib compared with placebo in all patients (median PFS 10.8 vs. 5.4 months, HR 0.36; 95% CI:0.30, 0.45; p<0.0001), in the HRD subgroup (median PFS 13.6 vs. 5.4 months, HR 0.32; 95% CI: 0.24, 0.42; p<0.0001), and in the tBRCA subgroup (median PFS 16.6 vs. 5.4 months, HR 0.23; 95% CI: 0.16, 0.34; p <0.0001).

The FDA also concurrently approved the complementary diagnostic test, FoundationFocusTM CDx BRCA LOH, for tumor samples to determine HRD status.

In ARIEL3, the most common adverse reactions in at least 20% of patients treated with rucaparib included nausea, fatigue (including asthenia), abdominal pain/distension, rash, dysgeusia, anemia, ALT/AST elevation, constipation, vomiting, diarrhea, thrombocytopenia, nasopharyngitis/URI, stomatitis, decreased appetite, and neutropenia. Myelodysplastic syndrome and/or acute myeloid leukemia occurred in 7 of 372 (1.9%) patients treated with rucaparib and in 1 of 189 (0.5%) patients assigned to placebo. Discontinuation due to adverse reactions occurred in 15% of patients receiving rucaparib and 2% of those assigned to placebo.

The recommended rucaparib dose is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.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

Rucaparib for Maintenance Treatment of Recurrent Ovarian (Epithelial, Fallopian Tube, or Primary Peritoneal) Cancer in Patients Who Are in Complete or Partial Response to Platinum-Based Chemotherapy

Author: Ekim Ekinci, PharmD MS
PGY-2 Oncology Pharmacy Resident
Houston Methodist Hospital
Houston, TX

What is the potential role for rucaparib in the treatment of recurrent ovarian cancer in patients who have had a complete or partial response to platinum-based chemotherapy?

  • The U.S. Food and Drug Administration (FDA) approved rucaparib on April 6, 2018, for the maintenance treatment of recurrent ovarian cancer (epithelial, fallopian tube, or primary peritoneal) in patients who had had a complete or partial response to platinum-based chemotherapy.1
  • Rucaparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. PARP is a family of enzymes activated in response to single-stranded damage of DNA.2 When PARP is inhibited by rucaparib, single-stranded breaks persist and result in stalled replication forks and double-stranded breaks.2
  • Approval was based on ARIEL3, an international multicenter randomized double-blind placebo-controlled trial; patients were randomly placed (2:1) in two groups: 375 patients receiving rucaparib and 189 patients receiving placebo.1,3
    • The primary outcome was investigator-assessed progression-free survival (PFS), evaluated in three nested cohorts: patients with BRCA mutations (germline or somatic), patients with homologous recombinant deficiencies (BRCA mutant or BRCA wild type and high loss of heterozygosity), and the intention-to-treat (ITT) population (BRCA mutant and BRCA wild type).3
      • Median PFS in the BRCA-mutant cohort was 16.6 months with rucaparib versus 5.4 months with placebo.3
      • Median PFS in the homologous recombinant-deficient cohort was 13.6 months with rucaparib versus 5.4 months with placebo.3
      • Median PFS in the ITT cohort was 10.8 months with rucaparib versus 5.4 months with placebo.3
    • At the time of FDA approval for this indication, ARIEL3 overall survival data were not mature; a follow-up analysis will be reported in the future.3
    • The most common adverse events (AEs) of any grade for the rucaparib group versus the placebo group were nausea (75% vs. 37%), fatigue (69% vs. 44%), dysgeusia (39% vs. 7%), anemia or decreased hemoglobin concentration (37% vs. 6%), constipation (37% vs. 24%), and vomiting (37% vs. 15%), respectively.3
    • Treatment-emergent AEs of grade 3 or higher were reported in 56% of patients in the rucaparib group versus 15% of patients in the placebo group.3
      • The most common were anemia or decreased hemoglobin concentration (19% vs. 1%) and increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations (10% vs. none).3
        • In the rucaparib group, a decline in hemoglobin concentration from baseline generally occurred in the first few cycles of treatment.3
        • Elevations in ALT or AST were generally transient, self-limiting, and not associated with other signs of liver toxicity.3
    • Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were reported in three (1%) patients in the rucaparib group and none in the placebo group.3
    • Treatment discontinuation due to AE occurred in 13% in the rucaparib arm versus 2% in the placebo arm.3
  • Other drugs in the PARP inhibitor class that have FDA indications include olaparib and niraparib.4-6 Talazoparib is another PARP inhibitor that may gain FDA approval in the near future.
    • All currently approved PARP inhibitors (olaparib, niraparib, and rucaparib) are indicated for maintenance treatment of recurrent ovarian cancer in patients who are in complete or partial response to platinum-based chemotherapy.4-6
      • No head-to-head trials have compared olaparib, niraparib, and rucaparib for this indication.7
      • All three are listed in the National Comprehensive Cancer Network guidelines for this indication.7
    • Olaparib also carries an FDA indication for treating breast cancer.5

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

  • Dosing for rucaparib is 600 mg by mouth twice daily until the disease progresses or an unacceptable level of toxicity is reached.4
    • No renal or hepatic dose adjustments are provided in the manufacturer’s labeling.
    • Rucaparib was not studied in patients with creatinine clearance less than 30 ml/min or in patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times the upper limit of normal).4
  • Rucaparib may be dose reduced for toxicities up to three times, after which discontinuation of the drug is recommended.4 Exact instructions on when to withhold or reduce the dose are not provided in the package insert. For secondary MDS/AML, permanently discontinue rucaparib. Recommended rucaparib dose reductions:
    • Starting dose: 600 mg twice daily
    • First dose reduction: 500 mg twice daily
    • Second dose reduction: 400 mg twice daily
    • Third dose reduction: 300 mg twice daily
  • Unlike olaparib, rucaparib does not carry dose adjustment recommendations when it is used concomitantly with moderate or strong CYP3A4 inhibitors or inducers.4,5 However, rucaparib is a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2C19 and CYP3A4.4
  • Financial and reimbursement support information is available for eligible patients through the Rubraca Connections website (http://rubracaconnections.com).

Clinical Pearls

  • Rucaparib is also approved for the treatment of deleterious germline and somatic BRCA mutation–associated ovarian cancer (epithelial, fallopian tube, or primary peritoneal) in patients who have been treated with 2 or more prior lines of chemotherapy.4
    • Although patients should be selected for treatment using the FDA-approved FoundationFocus CDxBRCA companion diagnostic test for the above indication, selection is not needed for the management of the indication (recurrent ovarian cancer) discussed in this update because use of rucaparib has shown PFS benefit in all nested cohorts, including in patients with no BRCA mutations.3,4,8
    • For the management of recurrent ovarian cancer, the FDA concurrently approved the complementary diagnostic test FoundationFocus CDxBRCA LOH.1 The test may be used on tumor samples to determine homologous recombination deficiency status and to inform discussions on prognosis; however, the test is not mandatory for the management of maintenance treatment.1,4
  • Rucaparib comes in three tablet strengths: 200 mg, 250 mg, and 300 mg.4
    • Tablets should be stored at room temperature.4
    • Tablets should be administered twice daily (~12 hours) with or without food.4
  • Niraparib is dosed once daily, whereas olaparib and rucaparib are dosed twice daily.4-6
  • Rucaparib is associated with moderate to high emetic potential; antiemetics may be needed to prevent nausea and vomiting. If a patient vomits after ingesting a dose, the dose should not be repeated.4,9
  • Although olaparib, niraparib, and rucaparib have not been studied head to head, comparisons of AE incidence for these three medications that may be of interest to pharmacists are listed below.
    • Moderate to high emetic potential and anemia seem to be class effects among PARP inhibitors, with relatively similar incidences observed among the different agents in approval trials.
    • Niraparib seems to be more myelosuppressive than olaparib and rucaparib. Incidence of neutropenia and thrombocytopenia seen with niraparib is numerically higher than that seen with olaparib or rucaparib (grade 3 or higher neutropenia: 5% with olaparib, 7%–10% with rucaparib, and 20% with niraparib; grade 3 or higher thrombocytopenia: 1% with olaparib, 5% with rucaparib, and 34% with niraparib).4-6
    • Incidence of transaminase elevations is highest with rucaparib (all grades: 41%–74%), compared to niraparib (all grades: 10%–36%) and olaparib (not reported).4-6
    • Elevations in cholesterol (all grades: 40%) and photosensitivity (all grades: 10%) are two AEs that have been reported with rucaparib, but not with olaparib or niraparib. 4-6
    • Price comparisons may be made by contacting each patient’s insurance company to determine which of the PARP inhibitors are on formulary and what the out-of-pocket cost will be for the patient for whom the medication is being considered.

References

  1. U.S. Food and Drug Administration. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm603997.htm. Updated April 6, 2018. Accessed May 19, 2018.
  2. Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005;7(4):1-20.
  3. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2017;390:1949-1961.
  4. Rubraca (rucaparib) [package insert]: Clovis Oncology, Inc., Boulder, CO: April 2018. Available at http://clovisoncology.com/files/rubraca-prescribing-info.pdf. Accessed May 19, 2018.
  5. Lynparza (olaparib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP, January 2018. Available at https://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf. Accessed May 23, 2018.
  6. Zejula (niraparib) [package insert]. Waltham, MA: Tesaro Inc., August 2017. Available at https://www.zejula.com/application/files/1715/2156/1557/prescribing_information.pdf. Accessed May 23, 2018.
  7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Ovarian Cancer (Including Fallopian Tube Cancer and Primary Peritoneal Cancer). Version 2.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed May 21, 2018.
  8. U.S. Food and Drug Administration. Rucaparib. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm533891.htm. Updated May 18, 2017. Accessed May 23, 2018.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Antiemesis. Version 2.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 23, 2018.

December 19, 2016 with PAP

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf

On December 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to rucaparib (RUBRACA™, Clovis Oncology Inc.) for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.

In conjunction with the drug approval, FDA approved the FoundationFocus™ CDxBRCA test (Foundation Medicine Inc.), the first FDA-approved next-generation sequencing (NGS)-based companion diagnostic to identify patients with advanced ovarian cancer eligible for treatment with rucaparib. The test detects alterations in BRCA1 and BRCA2 genes in the tumor tissue of ovarian cancer patients.

Approval of rucaparib and the FoundationFocus CDxBRCA test was based on data from two multicenter, single-arm, open label clinical trials that evaluated the efficacy of rucaparib in 106 patients with advanced ovarian cancer who had progressed after treatment with two or more prior chemotherapies. During enrollment, BRCA1/2 status was determined using either local germline BRCA test results or a Foundation Medicine clinical trial assay. Formalin-fixed paraffin-embedded tumor tissue samples were collected for testing with the companion diagnostic. Tumor BRCA mutation status was verified retrospectively in 96% (64/67) of the patients for whom a tumor tissue sample was available by the FoundationFocus CDxBRCA test.

All 106 patients received rucaparib 600 mg orally twice daily. Objective response rate (ORR) and duration of response (DoR) were assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Investigator-assessed ORR was 54% (57/106; 95% CI: 44-64%). Median DoR for the 57 responders (investigator-assessed) was 9.2 months (95% CI: 6.6, 11.6). ORR (investigator-assessed) was 66% (52/79; 95% CI: 54‑76%) in platinum-sensitive patients, 25% (5/20; 95% CI: 9-49%) in platinum-resistant patients, and 0% (0/7; 95% CI: 0-41%) in platinum-refractory patients. ORR was similar for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

The safety of rucaparib was evaluated in 377 patients with advanced ovarian cancer. The most common adverse reactions (greater than or equal to 20%) experienced by patients were nausea, fatigue (including asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Adverse reactions led to dose discontinuation in 10% of patients, most frequently from fatigue/asthenia (2%).

Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) was reported in 2 of 377 (0.5%) patients with ovarian cancer. In addition, AML was reported in 2 (<1%) patients with ovarian cancer enrolled in a blinded, randomized trial evaluating rucaparib versus placebo. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and use of rucaparib should be discontinued if MDS/AML is confirmed.

The recommended dose and schedule for rucaparib is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.

FDA granted the rucaparib application breakthrough therapy designation, priority review status, and orphan drug designation. This application was approved two months before the PDUFA goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.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 Application to Practice

Rucaparib (Rubraca®) for Ovarian Cancer

Author: Carolyn Oxencis, PharmD BCOP BCPS
Clinical Oncology Pharmacist
Froedtert and the Medical College of Wisconsin Department of Pharmacy
Milwaukee, WI

What is the potential role for nivolumab in the treatment of ovarian cancer?

  • The FDA granted rucaparib accelerated approval on December 19, 2016, for the treatment of BRCA-positive advanced ovarian cancer in patients who have received at least two prior chemotherapy regimens.1
    • The FDA previously granted rucaparib breakthrough therapy designation, priority review status, and orphan drug designation based on data from two phase 1/2 multicenter, single-arm, open label clinical trials assessing objective response rate (ORR) and duration of response (DOR).1,5
    • One of the trials included only platinum-sensitive patients, while the ARIEL2 study enrolled patients who were platinum sensitive, resistant, or refractory.3-5
      • Among the 42 patients in the phase 1/2 study, the ORR was 60%. The median DOR was 7.8 months.3
      • In the ARIEL2 trial, the ORR was 50%. The median DOR was 11.6 months.4-5
  • Rucaparib monotherapy provides a third-line option for advanced ovarian cancer patients with either a germline or a somatic mutation of BRCA, after two or more chemotherapy regimens.1
  • Rucaparib is the second poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor approved to treat advanced ovarian cancer patients.3,4

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

  • Pharmacists should be aware of the indications, dosing, and adverse-effect profile for FDA-approved PARP inhibitors.
    • The recommended dose and schedule for rucaparib is 600 mg (two 300-mg tablets) taken orally twice daily, with or without food.6
    • There are no dose adjustments for rucaparib for mild to moderate renal impairment or CYP450 enzyme interactions.6
    • Common adverse reactions (in 20% or more) include nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea.3,4
      • Dose-adjustment recommendations are available in the package insert for adverse reactions.6
      • Rucaparib is also available in a 200-mg tablet to accommodate recommended dose modifications.6
  • Patients should be advised to use appropriate sun protection because of their increased susceptibility to sunburn.6
  • Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and rucaparib should be discontinued if myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) develops.6

Clinical Pearls

  • About 15%–20% of ovarian cancer patients have the BRCA gene mutation.1
  • Patients should be selected for treatment using the FDA-approved FoundationFocus™ CDxBRCA as a companion diagnostic to detect deleterious BRCA1 and BRCA2 mutations in tumor tissue. This test is the first next-generation sequencing-based companion diagnostic to gain FDA approval.1,2,6
  • Under the FDA’s accelerated approval program, rucaparib was approved on the basis of data that suggest but do not confirm that the drug provides clinical benefits to patients. Continued approval of rucaparib is contingent on the results of a confirmatory trial.1

References

  1. U.S. Food and Drug Administration. Rucaparib. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm533891.htm. Updated December 19, 2016. Accessed January 27, 2017.
  2. Foundation Medicine, Inc. FoundationFocus™ CDxBRCA. www.foundationmedicine.com/focus/ Accessed January 30, 2017.
  3. ClinicalTrials.gov. A Study of Oral Rucaparib in Patients with a Solid Tumor (Phase I) or with gBRCA Mutation Ovarian Cancer (Phase II). Updated July 2016. https://clinicaltrials.gov/ct2/show/NCT01482715. NLM identifier: NCT01482715.
  4. A Study of Rucaparib in Patients with Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2). https://clinicaltrials.gov/ct2/show/NCT01891344?term=NCT01891344&rank=1. NLM Identifier: NCT01891344.
  5. McNeish IA, Oza AM, Coleman Rl, et al. Results of ARIEL2: A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. Presented at 2015 ASCO Annual Meeting. May 29–June 2, 2015; Chicago, IL. J Clin Oncol. 2015;33 (suppl; abstr 5508).
  6. Rubraca® [package insert]: Clovis Oncology, Inc., Boulder, CO; December 2016. www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf. Accessed January 27, 2017.
xs
sm
md
lg