Niraparib Demonstrates Antitumor Activity in Heavily Pretreated mCRPC With BRCA Mutations

Matthew R. Smith, MD

The PARP inhibitor niraparib (Zejula) elicited a meaningful overall response rate (ORR) in patients with heavily pretreated metastatic castration-resistant prostate cancer (CRPC) and DNA repair gene defects (DRDs), particularly those with BRCA alterations, according to data from the phase 2 GALAHAD trial (NCT02854436) published in The Lancet.¹

At a median follow-up of 10.0 months (interquartile range, 6.6-13.3), evaluable patients with BRCA alterations and measurable disease (n = 76) achieved an ORR of 34.2% (95% CI, 23.7%-46.0%) with the PARP inhibitor, meeting the primary end point of the trial. In this cohort, 3% experienced a complete response (CR), and 32% had a partial response (PR). Among evaluable patients with non–BRCA-altered measurable disease (n = 47), niraparib produced an ORR of 10.6% (95% CI, 3.5%-23.1%). In this cohort, no CRs were achieved, and 11% experienced PRs.

“The activity of niraparib in the measurable BRCA cohort is notable given the heavily pretreated, end-stage patient population with few therapeutic options,” lead study author Matthew R. Smith, MD, of Massachusetts General Hospital Cancer Center, and colleagues, wrote in the paper. “These findings are especially remarkable considering the high percentage of patients with visceral metastasis, in particular to the liver, which is strongly associated with poor survival; the high percentage of patients with 3 or more lines of previous therapy; and that some patients in the BRCA cohort even achieved a CR.”

Few therapeutic options are available for patients with CRPC who have progressed on a next-generation androgen signaling inhibitor and taxane chemotherapy.² Furthermore, DRDs are found in 12% to 23% of tumors in patients with metastatic disease, and these alterations are associated with poor prognosis and potential resistance to systemic therapies.³

Prior studies have investigated PARP inhibitors such as olaparib (Lynparza), rucaparib (Rubraca), and talazoparib (Talzenna). Niraparib is currently approved by the FDA for use in the maintenance treatment of select patient populations with ovarian, fallopian tube, and primary peritoneal cancers. In GALAHAD, investigators set out to explore the safety and activity of this PARP inhibitor in select patients with metastatic CRPC.

The study enrolled male patients who were at least 18 years of age, who had histologically confirmed metastatic CRPC with a predefined DRD and whose disease had progressed on an androgen signaling inhibitor and taxane chemotherapy in the form of docetaxel, cabazitaxel, or both. Patients also needed to have an ECOG performance status of 0 to 2.

Patients could not have previously received treatment with a PARP inhibitor or platinum-based chemotherapy, nor could they have a known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

To enter the screening phase of the trial, a deleterious germline or somatic alteration needed to be detected in at least 1 of the following genes: ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, and PALB2. DRD positivity was defined has having an alteration with known pathogenic consequences such has homozygous deletions, rearrangements, and nonsense, missense, frame-shift, and splice-site mutations. Patients with germline BRCA1 or BRCA2 alterations comprised the BRCA cohort, and those with other prespecified non-BRCA mutations comprised the non-BRCA cohort.

All patients were administered oral niraparib at a daily dose of 300 mg for 28-day cycles until treatment discontinuation due to progressive disease, intolerable toxicity or adverse effects (AEs), diagnosis of MDS or AML, investigator decision in the best interest of the patient, patient withdrawal of consent, death, or study termination. Dose adjustments or interruptions were made at the discretion of the investigator, based on severity of AEs.

CT or MRI and technetium bone scans were performed during screening, every 8 weeks for 24 weeks, and then every 12 weeks thereafter. Circulating tumor cell (CTC) counts were measured every cycle until cycle 7, then at the end of treatment. PSA assessments were conducted every 4 weeks until cycle 7, then every 3 cycles.

The primary end point of the trial was investigator-assessed ORR in patients who comprised the measurable BRCA cohort. Notably, the primary end point was amended early in the study from a composite response end point to ORR.

Secondary end points included ORR in patients who comprised the non-BRCA cohort, CTC response, overall survival (OS), radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, time to symptomatic skeletal event, duration of response (DOR), and safety. Prespecified exploratory end points included composite response rate, CTC conversion, or at least a 50% decline in PSA.

Of 385 patients screened for the trial, 289 were enrolled. All 289 patients were included in the safety analysis, and 223 patients were included in the efficacy analysis, based on DRD eligibility; 142 patients comprised the BRCA cohort and 81 comprised the non-BRCA cohort. Moreover, 76 patients were in the measurable BRCAcohort, and 47 patients were in the measurable non-BRCA cohort.

Study participants were noted to be heavily pretreated and to have advanced disease in both the BRCA and non-BRCA cohorts. Most patients had bone metastases and a notable proportion of those in the primary efficacy population had visceral disease, which included liver and lung metastases. Moreover, many patients had nodal disease.

Sixty-three percent of the 289 patients included in the safety analysis were noted to have previously received at least 3 systemic therapies for metastatic disease; 33% had received 2 androgen signaling inhibitors, and 37% had received 2 taxane-based therapies.

In the measurable BRCA cohort, the CTC response rate was 25% (n = 18/71), the median OS was 10.87 months (range, 9.49-13.77), median rPFS was 5.52 months (range, 5.29-7.59), median time to radiographic progression was 5.55 months (range, 5.36-8.08), median time to PSA progression was 5.5 months (range, 4.60-8.31), median time to symptomatic skeletal event was 13.80 months (range, 9.07–not evaluable [NE]), and the median DOR was 5.55 months (range, 3.91-7.20). Additionally, the composite response rate was 61% (n = 46/76; 95% CI, 48.7%-71.6%), CTC conversion rate was 44% (n = 28/64; 95% CI, 31.4%-56.7%), and the PSA decline rate was 41% (n = 31/76; 95% CI, 29.7%-52.7%).

In the BRCA cohort without measurable disease (n = 142), the CTC response rate was 24% (n = 31/131), median OS was 13.01 months (range, 11.04-14.29), median rPFS was 8.08 months (range, 5.55-8.38), median time to radiographic progression was 8.08 months (range, 5.75-8.97), median time to PSA progression was 5.13 months (range, 4.60-5.59), median time to symptomatic skeletal event was 13.80 months (range, 10.41-NE), and the median DOR was 6.28 months (range, 3.65-9.23). In this cohort, the composite response rate was 58% (n = 82/142; 95% CI, 49.2%-66.0%), the CTC conversion rate was 47% (n = 55/117; 95% CI, 37.7%-56.5%), and the PSA decline rate was 43% (n = 61/142; 95% CI, 34.7%-51.5%).

Lastly, in the non-BRCA cohort (n = 81), the CTC response rate was 8% (n = 6/71), median OS was 9.63 months (range, 8.05-13.44), median rPFS was 3.71 months (range, 1.97-5.49), median time to radiographic progression was 3.78 months (range, 2.00-5.55), median time to PSA progression was 3.65 months (range, 2.83-3.71), median time to symptomatic skeletal event was 10.35 months (range, 8.18-NE), and the median DOR was 5.16 months (range, 2.14-NE). In this group, the composite response rate was 15% (n = 12/81; 95% CI, 7.9%-24.5%), the CTC conversion rate was 15% (n = 9/60; 95% CI, 7.1%-26.6%), and the PSA decline rate was 5% (n = 4/81; 95% CI, 1.4%-12.2%).

Regarding safety, 288 patients experienced at least 1 treatment-emergent AE. The most common AEs of any grade were nausea (58%), anemia (54%), and vomiting (38%). Grade 3 or higher AEs occurred in 75% of patients, with the most common including anemia (33%), thrombocytopenia (16%), and neutropenia (10%).

Furthermore, 46% of patients experienced at least 1 serious treatment-emergent AE (TEAE), and 15% of patients had serious TEAEs associated with the study drug, the most common of which were thrombocytopenia and anemia. One patient experienced grade 5 anemia, and 4 patients had a grade 5 AE of general physical health deterioration.

Moreover, 44% of patients experienced an AE that led to dose reduction, and 13% of patients discontinued treatment due to drug-related toxicities. Sixteen deaths were related to AEs, with 2 deemed to potentially be related to niraparib. Seventy-two percent of patients died during the study.

Additional studies investigating niraparib-based regimens in appropriate biomarker-identified populations at earlier stage of disease are ongoing. For example, the phase 3 MAGNITUDE trial (NCT03748641) is examining niraparib in combination with abiraterone acetate (Zytiga) plus prednisone in the first-line treatment of patients with CRPC with or without DRD. Additionally, the phase 3 AMPLITUDE trial (NCT04497844) is investigating niraparib in combination with abiraterone acetate plus prednisone in a biomarker-selected population with metastatic castration-sensitive disease.

“Such findings underscore the need for, and importance of, molecular testing to inform management along with continued research to establish treatment paradigms with appropriately targeted therapies for patients with prostate cancer,” the study authors concluded. “Efforts to investigate and better understand predictive markers and signatures of both response and resistance to treatment with PARP inhibitors such as niraparib are needed to guide therapy selection and optimize treatment outcomes.”

References

1. Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet. Published online February 4, 2022. doi:https://doi.org/10.1016/S1470-2045(21)00757-9
2. Gillessen S, Attard G, Beer TM, et al. Management of patients with advanced prostate cancer: report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol. 2020;77(4):508-547. doi:10.1016/j.eururo.2020.01.012
3. Warner EW, Yip SM, Chi KN, et al. DNA repair defects in prostate cancer: impact for screening, prognostication and treatment. BJU Int. 2019;123(5):769-776. doi:10.1111/bju.14576