Summary

• Niraparib is an orally bioavailable poly (ADP-ribose) polymerase (PARP) inhibitor that was evaluated for monotherapy treatment in the following study.¹
• GALAHAD (NCT02854436) was a phase 2, open-label, multinational study evaluating the safety and efficacy of niraparib monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and germline or somatic biallelic pathogenic DNA-repair gene defects (DRD) in BRCA1/2 or other nonBRCA genes who had disease progression on or after androgen signaling inhibitor therapy and taxane-based chemotherapy.^2-5
  • After a median follow up of 10 months, 34.2% (26/76) patients met the primary endpoint of objective response rate (ORR) in patients with BRCA DRD and measurable disease. The ORR in nonBRCA patients with measurable disease was 10.6% (5/47) after a median follow up of 8.6 months. The median treatment duration in the BRCA cohort was 6.5 months (interquartile range [IQR], 3.3-9.4) and in the nonBRCA cohort was 3.6 months (IQR, 1.8-5.6). In the BRCA cohort, the median radiographic progression-free survival (rPFS) was 8.08 months (95% CI, 5.55-8.38), and the median overall survival (OS) was 13.01 months (95% CI, 11.04-14.29). The median rPFS and OS in the nonBRCA cohort were 3.71 months (95% CI, 1.97-5.49) and 9.63 months (95% CI, 8.05-13.44), respectively. Efficacy results are summarized in Table: Objective Response Rates and Table: Prespecified Secondary and Exploratory Efficacy Endpoints.⁵
  • A summary of adverse events (AEs) is provided in Table: Summary of Adverse Events. The most common AEs of any grade were nausea (n=169, 58%), anemia (n=156, 54%), and vomiting (n=111, 38%). Grade ≥3 anemia, thrombocytopenia, and neutropenia were reported in 33%, 16%, and 10% of patients, respectively. The most common grade 3/4 nonhematologic AEs were fatigue (n=19, 7%) and nausea (n=15, 5%). AEs leading to discontinuation were observed in 12.8% of patients, including thrombocytopenia (n=10, 3.5%) and anemia (n=7, 2.4%).^5,6
• Additional analyses that evaluated circulating tumor cell (CTC) count conversion, health-related quality of life (HRQoL) outcomes, and the relationship between BRCA1/2 reversion mutations with treatment response in the GALAHAD study are described below.^3,7-9
• Preliminary efficacy and safety data were previously presented for 50 participants with mCRPC and biallelic DRD.⁴

CLINICAL DATA

GALAHAD Study

Smith et al (2022)⁵ reported the efficacy and safety results of niraparib monotherapy in patients with mCRPC and germline or somatic biallelic pathogenic alterations in BRCA1/2 or other nonBRCA genes who had disease progression on or after androgen signaling inhibitor therapy and taxane-based chemotherapy.

Study Design/Methods

• Phase 2, open-label, single-arm, multinational study
• Patients were prescreened using a blood or tissue sample for the evaluation of DRD alterations in at least one of the following genes: ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, and PALB2.
• Patients received niraparib 300 mg orally once daily in 28-day cycles. Treatment continued until discontinuation due to disease progression, unacceptable toxicity, diagnosis of myelodysplastic syndrome or acute myeloid leukemia, or death.
• Tumor assessment was performed every 8 weeks for the first 24 weeks, and then every 12 weeks while on treatment and included chest, abdomen and pelvis computed tomography (CT)/magnetic resonance imaging (MRI) and bone scan (^99mTc).
• Select inclusion criteria: men diagnosed with mCRPC and DRD; disease progression on an androgen signaling inhibitor and taxane-based chemotherapy; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2.
• Select exclusion criteria: prior treatment with a PARP inhibitor or platinum-based chemotherapy; and prior or current myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Primary endpoint: investigator-assessed ORR (defined by proportion of patients with a confirmed partial or complete response as defined by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 with no evidence of bone progression as per Prostate Cancer Working Group 3 [PCWG3] criteria) in patients with BRCA DRD and measurable disease.
• Key secondary endpoints: ORR by RECIST/PCWG3 criteria in biallelic nonBRCA patients, CTC response (CTC=0/7.5 mL blood at 8 weeks post-baseline in patients with baseline CTC >0), OS, rPFS, time to radiographic progression, time to prostate-specific antigen (PSA) progression, time to symptomatic skeletal event, and duration of objective response, and safety.

Results

Patient Characteristics

• A total of 289 patients with mCRPC and DRD alterations were enrolled. Patient baseline characteristics are described in the Table: Select Baseline Characteristics.
  • Based on modified DRD eligibility, 223 (77%) patients were analyzed in the efficacy analysis, of which 142 and 81 patients had BRCA and nonBRCA alterations, respectively.
  • A total of 76 patients with BRCA DRD alterations and 47 with nonBRCA DRD alterations had measurable disease at baseline.
• Of the 289 enrolled patients, 63% had received 3 or more prior therapies for prostate cancer.
• In the efficacy analysis population, 23% (n=33) and 25% (n=20) of BRCA and nonBRCA patients had visceral metastases, respectively.

Efficacy

• The median treatment duration in the BRCA cohort was 6.5 months (IQR, 3.3-9.4) and in the nonBRCA cohort was 3.6 months (IQR, 1.8-5.6).
• After a median follow up of 10 months, in patients with BRCA DRD alterations and measurable disease, ORR was 34.2% (n/N=26/76; 95% CI, 23.7-46.0). The median duration of objective response was 5.55 months (95% CI, 3.9-7.2). ORR are described in the Table: Objective Response Rates.
  • A total of 36 patients (46%) had a decrease of 30% or more from baseline in the sum of longest target lesion diameters.
  • The median rPFS and OS were 5.52 months (95% CI, 5.29-7.59) and 10.87 months (95% CI, 9.49-13.77), respectively.
• After a median follow up of 8.6 months, in patients with nonBRCA DRD alterations and measurable disease, ORR was 10.6% (n/N=5/47; 95% CI, 3.5-23.1). The median duration of objective response in the nonBRCA cohort was 5.16 months (95% CI, 2.14-NE).
  • The median rPFS and OS were 3.71 months (95% CI, 1.97-5.49) and 9.63 months (95% CI, 8.05-13.44), respectively.
• In the BRCA cohort, the median rPFS was 8.08 months (95% CI, 5.55-8.38), and the median OS was 13.01 months (95% CI, 11.04-14.29).

Safety

• In the safety population (n=289), 288 patients had one or more TEAE. A summary of AEs is reported in Table: Summary of Adverse Events.
  • The most common AEs (of any grade) were nausea (n=169; 58%), anemia (n=156; 54%), and vomiting (n=111; 38%).
  • Grade ≥3 anemia, thrombocytopenia, and neutropenia were reported in 33%, 16%, and 10% of patients, respectively.
  • The most common grade 3/4 nonhematologic TEAEs were fatigue (n=19; 7%) and nausea (n=15; 5%).
• Of the 76 patients with BRCA alterations and measurable disease (primary efficacy cohort), 7 patients discontinued therapy prior to their first study evaluation due to: progressive disease (n=4); withdrawal of consent (n=1); use of radium-223 for bone disease burden (n=1); and urosepsis resulting in death (n=1).
• Treatment was discontinued in 271 of 289 (93.8%) patients; 70.9% (n=205) due to progressive disease and 14.2% (n=41) due to AEs.⁶
  • AEs leading to discontinuation were observed in 37/289 (12.8%) of patients; thrombocytopenia (n=10; 3.5%) and anemia (n=7; 2.4%) were most frequently cited.
• AEs leading to death were observed in 16 (5.5%) patients and were due to: disease progression (general physical health deterioration, metastases; n=7); sepsis (sepsis, neutropenic sepsis, septic shock, urosepsis; n=5); cardiac event (cardiac arrest, cardiac failure, cardiac failure congestive; n=3); anemia, hypocalcemia, and hematuria (n=1).⁶
  • Two AEs with fatal outcomes (sepsis and urosepsis) were considered by the sponsor to be possibly related to niraparib treatment.

Additional Analyses

• An interim analysis evaluated CTC conversion (defined as CTC decrease to <5 for patients with baseline CTC ≥5, with confirmation at ≥28 days) and CTC0 (defined as CTC=0 for patients with baseline CTC ≥5) rates in patients enrolled in the GALAHAD study with BRCA biallelic DRD.³
  • Of the 60 patients with BRCA biallelic DRD, 37 (62%) and 23 (38%) patients had measurable and non-measurable disease, respectively. The median CTC value at baseline was 35 (range, 0-1542), of which 51 patients had a ≥5 CTC value at baseline.
  • In patients with measurable or non-measurable disease and BRCA biallelic DRD, CTC conversion rates were similar (Table: CTC Conversion Rates in Patients with BRCA Biallelic DRD). Among patients with measurable disease, the ORR, as described in Table: Objective Response Rates, is similar to the CTC conversion rate.
  • Grade 3 or 4 AEs occurred in 46 (76.7%) patients; the most common (≥8% of patients) grade 3-4 AEs included: anemia (n=21 [35.0%]),
    thrombocytopenia (n=5 [8.3%]), neutropenia (n=6 [10.0%]), and hypertension (n=5 [5.3%]) in the 60 evaluable patients.
  • Treatment discontinuation due to AEs occurred in 10 patients (16.7%). Anemia was the most common AE leading to discontinuation (n=2, 3.3%).
  • AEs were associated with death in 2 patients: seizure and urosepsis.

• An analysis evaluated overall HRQoL, pain intensity, and pain interference, which were prespecified study endpoints, in the intent-to-treat (ITT) efficacy population in the GALAHAD study. Patient-reported outcomes (PROs) were assessed at baseline; cycles 3, 5, and 7; and then every third cycle until the end of treatment; however, the number of respondents was small and not meaningfully evaluable beyond cycle 10.^7,8
  • Of the 223 patients in the ITT efficacy analysis, 221 completed the HRQoL evaluations at baseline and had ≥1 post-baseline evaluations. Additionally, assessment compliance was between 84.3% and 97.7% in the BRCA cohort and between 87.5% and 100.0% in the nonBRCA cohort from baseline through cycle 10.
  • Changes from baseline were compared using a mixed-effect model for repeated measures based on Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores. On average, HRQoL improved in the BRCA cohort by cycle 3 (mean change, 6.03; 95% CI, 2.76-9.29) and was maintained above baseline until cycle 10 (mean change, 2.84; 95% CI, -1.95 to 7.63), whereas the nonBRCA cohort showed no early change in HRQoL from baseline (mean change, -0.07; 95% CI, -4.69 to 4.55) and declined by cycle 10 (mean change, -5.10; 95% CI, -15.3 to 5.06).
  • Median time to deterioration in the FACT-P total score was numerically longer in the BRCA cohort (8.31 months; IQR, 0-21.9) compared with the nonBRCA cohort (3.71 months; IQR, 0-12.0; HR, 0.419; 95% CI, 0.276-0.636). In both treatment groups, <50% of patients experienced clinically meaningful deterioration at the time of analysis; therefore, median time to deterioration in pain intensity and pain interference could not be estimated in either cohort.
  • Patients in both the BRCA and nonBRCA cohorts experienced rapid reduction in pain scores by cycle 3 as measured by Brief Pain Inventory Short Form (BPI-SF).
    • The BRCA cohort experienced greater early pain relief by cycle 3 (mean change,  -1.06; 95% CI, -1.40 to -0.72) compared with the nonBRCA cohort (mean change, -0.60; 95% CI, -1.08 to -0.13). Similar mean pain intensity reductions were observed in both cohorts at cycle 10 (BRCA, -0.29; 95% CI, -0.77 to -0.20; nonBRCA, -0.56; 95% CI, -1.61 to 0.50), but interpretation may be limited by sample size.
    • Pain interference was also rapidly reduced by cycle 3 in the BRCA cohort (-0.91; 95% CI, -1.32 to -0.50) and the nonBRCA cohort (-0.59; 95% CI, -1.16 to         -0.01), with differences that were maintained until cycle 5.
• Another analysis evaluated the relationship between BRCA reversion mutations and composite response (ORR, conversion of CTC from ≥5/7.5 mL to <5/7.5 mL of blood, or ≥50% decline in PSA [PSA50]) and rPFS in patients with BRCA1/2 alterations. Of the 33 patients that provided an end-of-treatment ctDNA sample, 28 patients developed at least 1 reversion mutation. Of the 28 patients with reversions, 5 patients were classified as low reversions. The median treatment duration in patients with reversion compared to no/low reversion was 6.9 months and 3.7 months, respectively. The composite response was 74.2% in patients with reversion compared to 25.8% in patients with no/low reversion. Patients with BRCA2 reversion had a longer median rPFS compared to patients with no/low reversion (8.1 months [95% CI, 6.2-NE] vs 5.5 months [95% CI, 1.8-NE]).⁹

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and other resources, including internal/external databases) was conducted on 09 August 2024.