FDA Grants Breakthrough Designation to Niraparib for Metastatic CRPC

The FDA has granted a breakthrough therapy designation to niraparib for the treatment of patients with <em>BRCA1/2</em>-mutated metastatic castration-resistant prostate cancer who have previously received taxane chemotherapy and androgen receptor&ndash;targeted therapy.

The FDA has granted a breakthrough therapy designation to niraparib (Zejula) for the treatment of patients withBRCA1/2-mutated metastatic castration-resistant prostate cancer (CRPC) who have previously received taxane chemotherapy and androgen receptor (AR)—targeted therapy.1

“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, said 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.”

The designation was based on findings from the ongoing multicenter, open-label phase II GALAHAD trial that is investigating the safety and efficacy of the PARP inhibitor in men with metastatic CRPC who have DNA repair abnormalities (NCT02854436). Findings from a prespecified interim analysis of the trial were recently presented at the 2019 ESMO Congress.2

The trial consists of a pre-screening phase for biomarker evaluation, a screening phase, a treatment phase, and a follow-up phase. Patients with metastatic CRPC who harbored DNA repair gene defects (DRD) and had previously progressed on ≥1 AR inhibitor and ≥1 taxane-based chemotherapy regimen were eligible for enrollment. Prior PARP inhibition or platinum-based chemotherapy was not allowed.

Objective response rate (ORR) by RECIST 1.1 criteria with no evidence of bone progression by Prostate Cancer Working Group 3 criteria in patients with biallelicBRCAis the primary endpoint of the trial. Secondary endpoints include ORR, overall survival (OS), radiographic progression-free survival (rPFS), duration of objective response, safety, and circulating tumor cell (CTC) response. Composite response rate (CRR) was defined in the study as ORR by RECIST 1.1 criteria, conversion of CTC to <5/7.5 mL blood, or prostate-specific antigen (PSA) decline ≥50%.

As of the data cutoff, 223 patients were screened and 165 of these patients were enrolled. Eighty-one patients (49.1%) had biallelic DRD, including 46 who hadBRCAand 35 who did not. Patients were followed for a minimum of 16 weeks.

Of the patients with biallelic DRD, the mean age was 68.2 years and about half of the patients (53%) had an ECOG performance status of 1 and a Gleason score ≥8 (64%). Disease progression was in the bone for the majority of patients (93%) at baseline. About one-third of patients (36%) had received 2 prior lines of therapy and 30% had received ≥4. Prior AR-targeted therapy consisted of abiraterone acetate (Zytiga) and prednisone in 67% and enzalutamide (Xtandi) in 65%. Prior chemotherapy consisted of docetaxel for 99% of patients and cabazitaxel in 40%.

The ORR was 41% (95% CI, 23.5%-61.1%), consisting of 1 complete response (CR) and 11 partial responses (PRs) in patients withBRCAbiallelic DRD. The CRR was 63% (95% CI, 47.6%-76.8%), which also consisted of a ≥50% decline in PSA in 50% of patients and CTC conversion to <5 CTCs in 47%. The median duration of response was 5.6 months (range, 3.5-9.2) and responses were ongoing in 7 of 12 patients as of the May 23, 2019, data cutoff date. The median rPFS was 8.2 months (95% CI, 5.2-11.1) and the median OS was 12.6 months (95% CI, 9.2-15.7).

In patients with non-BRCAbiallelic DRD, the ORR was 9% (95% CI, 1.1%-29.2%), including 2 PRs. The CRR was 17% (95% CI, 6.6%-33.7%), which also included PSA response in 3% and CTC conversion in 21%. The median rPFS was 5.3 months (95% CI, 1.9-5.7) and the median OS was 14.0 months (95% CI, 5.3-20.1). The median duration of response was not evaluable.

The median treatment duration among patients who responded to niraparib was 6.7 months (range, 2-27), and 66% of patients with biallelicBRCAhad a treatment duration lasting ≥6 months.

At least 1 adverse event (AE) was observed in 98% of all of the enrolled patients in the trial, and grade 3/4 AEs were seen in 70%. The most common grade 3/4 AEs included anemia in 29% and thrombocytopenia in 15%, but overall grade 3/4 events were mostly hematologic and could be managed with dose interruption or modification. Forty-two percent of patients had at least 1 serious AE.

AEs leading to discontinuation, including anemia in 7 patients and thrombocytopenia in 6, were reported in 20% of patients. AEs led to death in 9 total patients, due to general deterioration in 3; cardiac failure in 2; anemia, hypocalcemia, hematuria in 1 patient each; and urosepsis, seizure, and acute respiratory failure in 1 patient each.

Niraparib is 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 CR or PR to platinum-based chemotherapy. The PARP inhibitor continues to be investigated in patients with metastatic CRPC in the ongoing phase III MAGNITUDE trial (NCT03748641).


  1. Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Niraparib for the Treatment of Metastatic Castration-Resistant Prostate Cancer [press release]. Raritan, NJ: Janssen Pharmaceutical Companies of Johnson & Johnson; October 3, 2019. https://bit.ly/2pBBuvx. Accessed October 3, 2019.
  2. Smith MR, Sandhu SK, 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.