Advertisement

Rucaparib in BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer


Advertisement
Get Permission

On May 15, 2020, rucaparib was granted accelerated approval for the treatment of patients with deleterious BRCA mutation–associated (germline or somatic) metastatic castration-resistant prostate cancer who have been treated with androgen receptor–directed therapy and taxane-based chemotherapy.1,2

Supporting Efficacy Data

Approval was supported by findings in the ongoing multicenter phase II TRITON2 study (ClinicalTrials.gov identifier NCT02952534).2,3 In the trial, 115 patients with BRCA-mutated (germline or somatic) metastatic castration-resistant prostate cancer who had been treated with androgen receptor–directed therapy and taxane-based chemotherapy received oral rucaparib at 600 mg twice daily. Patients also either received concomitant gonadotropin-releasing hormone (GnRH) analog treatment or had prior bilateral orchiectomy. The efficacy analysis included 62 patients in the trial with measurable disease at baseline on independent radiology review.

Confirmed objective response on blinded independent radiology review according to modified Response Evaluation Criteria in Solid Tumors, version 1.1/Prostate Cancer Working Group 3 criteria was observed in 27 patients (44%, 95% confidence interval [CI] = 31%–57%). Median response duration was not reached (95% CI = 6.4 months to not estimable). Response durations ranged from 1.7 to 24+ months, with 15 responders (56%) having a response duration at least 6 months.

OF NOTE

Rucaparib has warnings/precautions for MDS/AML, including fatal cases, and embryofetal toxicity.

How It Works

Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3, which play a role in DNA repair. Studies in vitro have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage, apoptosis, and cancer cell death.

Increased rucaparib-induced cytotoxicity and antitumor activity were observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models with or without BRCA deficiencies.

How It Is Used

In the current indication, patients must be selected for treatment with rucaparib based on the presence of a deleterious BRCA mutation (germline and/or somatic). A U.S. Food and Drug Administration–approved test for the detection of BRCA1/BRCA2 mutations in patients with metastatic castration-resistant prostate cancer is not currently available.

The recommended dose of rucaparib is 600 mg twice daily, with or without food. Treatment should be continued until disease progression or unacceptable toxicity. Patients should receive concomitant treatment with a GnRH analog or should have had bilateral orchiectomy. For management of adverse reactions, interruption of treatment or dose reduction should be considered. Recommended dose reductions are sequentially to 500 mg twice daily, 400 mg twice daily, and 300 mg twice daily for first, second, and third reductions.

Coadministration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, and CYP2C19 substrates, which may increase the risk of toxicities of these drugs. The dosage of these substrates should be adjusted if clinically indicated.

Safety Profile

Safety data are derived from the total of 115 patients with BRCA-mutated metastatic castration-resistant prostate cancer who received rucaparib in the TRITON2 trial. The median duration of treatment was 6.5 months (range = 0.5–26.7 months).

KEY POINTS

  • Rucaparib was granted accelerated approval for treatment of patients with deleterious BRCA mutation-associated metastatic castration-resistant prostate cancer who have been treated with androgen receptor–directed therapy and taxane-based chemotherapy.
  • The recommended dose of rucaparib is 600 mg twice daily with or without food, with treatment continued until disease progression or unacceptable toxicity.

The most common adverse events of any grade (≥ 20% of patients) were fatigue/asthenia (62%), nausea (52%), anemia (43%), increased alanine transaminase (ALT)/aspartate transaminase (AST; 33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%). The most common grade 3 or 4 adverse events included anemia (25%), thrombocytopenia (10%), fatigue/asthenia (9%), and increased ALT/AST (5%). The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin (25%), decreased lymphocytes (17%), decreased phosphate (15%), decreased neutrophils (10%), and decreased platelets (10%).

Adverse events led to dose interruption in 57% of patients, with those requiring interruption in more than 3% of patients consisting of anemia, thrombocytopenia, fatigue/asthenia, nausea, vomiting, neutropenia, increased ALT/AST, increased creatinine, decreased appetite, acute kidney injury, and hypophosphatemia. Dose reductions due to adverse events occurred in 41% of patients, with those requiring reduction in more than 3% consisting of anemia (14%), fatigue/asthenia (10%), thrombocytopenia (7%), nausea (6%), decreased appetite (4%), and rash (3%).

Discontinuation of treatment due to adverse events was required in 8% of patients, with discontinuation being due to QT prolongation, acute respiratory distress syndrome, anemia, balance disorder, cardiac failure, decreased appetite/fatigue/weight, leukopenia/neutropenia, increased ALT/AST, and pneumonia in one patient each (< 1%). Adverse events led to death in two patients (1.7%); mortality was due to acute respiratory distress syndrome in one patient and pneumonia in one patient.

Rucaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, including fatal cases, and embryofetal toxicity. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter. Treatment should be interrupted or dose-reduced based on the severity of the reaction, and use of rucaparib should be discontinued if myelodysplastic syndrome/acute myeloid leukemia  is confirmed. Patients should be advised not to breastfeed while taking rucaparib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. Available at https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate. Accessed May 21, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Rubraca (rucaparib) tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s004lbl.pdf. Accessed May 21, 2020.

3. Abida W, Campbell D, Patnaik A, et al: Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer: Updated analyses. Ann Oncol 30:v327-v328, 2019.

 


Advertisement

Advertisement



Advertisement