FDA Grants Niraparib Breakthrough Designation for BRCA+ mCRPC

The FDA has granted a breakthrough therapy designation to the PARP inhibitor niraparib (Zejula) for the treatment of patients with BRCA1/2—mutant metastatic castration-resistant prostate cancer (mCRPC) who have previously received taxane-based chemotherapy and an androgen receptor (AR) inhibitor.

The decision is based on findings from the phase II GALAHAD study (NCT02854436), in which niraparib demonstrated a 41% objective response rate (ORR) in patients with mCRPC who have BRCA biallelic DNA-repair gene defects (DRD). The prespecified interim analysis of the trial was recently presented at the 2019 ESMO Congress.

"Niraparib is a PARP inhibitor that we believe may help address an important unmet need for patients with metastatic castration-resistant prostate cancer who have mutations in DNA-repair genes," Kiran Patel, MD, vice president, clinical development, solid tumors, Janssen Research & Development, LLC, the developer of niraparib, stated in a press release. "We are pleased with the FDA's Breakthrough Therapy Designation as we continue the clinical development of niraparib, and we look forward to working with the agency in our continued focus and commitment to bring new advancements to patients diagnosed with prostate cancer."

BRCA1/2 mutations are the most common DRD in patients with mCRPC, and patients with a DRD in BRCA1/2 are said to be at an elevated risk for both prostate cancer occurrence and more aggressive disease. Additionally, patients with mCRPC who experience disease progression after AR-targeted treatment and taxane-based chemotherapy also have a poor prognosis and there are few therapeutic options.

Breakthrough therapy designations are intended to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition.

In the ongoing, multicenter, open-label, GALAHAD trial, investigators evaluated the efficacy and safety of niraparib in the treatment of adult patients with mCRPC and DRD who had received treatment with next-generation AR-targeting therapies and docetaxel. The trial is being conducted in 14 countries.

To be eligible for enrollment, patients with mCRPC were biomarker positive for DRD and had progressed on ≥1 AR-targeted therapy and ≥1 taxane-based chemotherapy. No prior PARP inhibition or platinum-based chemotherapy was permitted, and patients could not have had a prior diagnosis of myelodysplastic syndromes or acute myeloid leukemia.

Investigators first conducted a biomarker evaluation to determine DRD status, followed by a 28-day screening phase. Niraparib was given at 300 mg once daily in 28-day cycles until end of treatment, and patients were followed up every 3 months until therapy was complete. The primary endpoint was ORR of soft tissue (visceral or nodal disease), as defined by RECIST1.1 criteria with no evidence of bone progression according to Prostate Cancer Working Group 3 criteria in those with biallelic BRCA mutations.

Secondary endpoints included ORR in patients with biallelic non-BRCA mutations, circulating tumor cell (CTC) response, overall survival (OS), radiographic PFS (rPFS), duration of objective response, and safety.

As of May 23, 2019, 223 patients were screened for eligibility and 165 patients with mCRPC and DRD were enrolled. Eighty-one patients had biallelic DRD with BRCA mutations (n = 46) and non-BRCA mutations (n = 35) at a minimum 16 weeks of follow-up.

The baseline characteristics were similar between the BRCA and non-BRCA biallelic DRD groups. The median age was 68.2 years, and more than half (53%) of patients had an ECOG performance status of 1. Most patients (93%) had disease progression in the bone, followed by the lymph node (49%), liver (24%), soft tissue (19%), and lung (15%).

All patients had ≥2 lines of prior therapy with ≥1 AR-targeted treatment and 1 line of taxane-based chemotherapy in the mCRPC setting. Of 81 patients with biallelic DRD, 51 (63%) had measurable disease at baseline (BRCA, n = 29; non-BRCA, n = 22). Forty-seven percent of patients had visceral metastases. Median follow-up period was 7.3 months and 6.4 months in patients with BRCA biallelic DRD and non-BRCA biallelic DRD, respectively. The median duration of treatment was 4.17 months (range, 0.4-27.0) in patients with biallelic DRD.

Niraparib was discontinued in 83% of patients, due to progression disease (74%) and adverse events (AEs; 17%).

Results showed that in those with BRCA biallelic DRD, the ORR was 41% and composite response rate was 63%. The 41% ORR also comprised a 50% prostate-specific antigen (PSA) response was 50%, and the CTC conversion rate was 47%. The median duration of objective response was 5.6 months (range, 3.5-9.2) and responses were ongoing in 7 of 12 patients. Moreover, the median rPFS and OS were 8.2 and 12.6 months, respectively.

The composite response rates in measurable and nonmeasurable patients with BRCA biallelic DRD was 66% and 59%, respectively.

In those with non-BRCA biallelic DRD, the ORR was 9% and the composite response rate was 17%. The durations of objective response for the 2 patients who responded were 3.8 and 6.5 months, and the median rPFS and OS were 5.3 and 14.0 months.

Regarding safety, the AEs associated with niraparib were consistent with what has been previously reported; no new safety signals were identified. In the safety population (n = 165), ≥1 AE were reported in 98% of patients. The grade 3/4 AEs were anemia (29%), thrombocytopenia (15%), neutropenia (7%), fatigue (6%), and back pain (6%). AEs that led to discontinuation occurred in 20% of patients and were due to anemia and thrombocytopenia.

AEs that led to death were reported in 5% (n = 9) of patients and were due to general physical health deterioration (n = 3), cardiac failure (n = 2); anemia, hypocalcemia, hematuria (n = 1); urosepsis, seizure and acute respiratory failure (n = 1 each). Two AEs that had fatal outcomes, seizure and urosepsis, were unexpected and were considered to be treatment-related.

Niraparib is also being evaluated in the phase III MAGNITUDE study (NCT03748641), which is evaluating the PARP inhibitor in combination with abiraterone acetate and prednisone in adults with metastatic prostate cancer, as well as the phase Ib/II QUEST trial (NCT03431350), which is looking at combination therapies with niraparib in mCRPC.

The PARP inhibitor is currently approved by the FDA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Smith MR, Sandhu S, Kelly WK, et al. Pre-specified interim analysis of GALAHAD: a phase 2 study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA50.