Niraparib Plus Hormone Therapy Improves rPFS in BRCA1/2-Altered mCRPC

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Enhanced rates of radiographic progression-free survival (rPFS) and improved clinical outcomes were observed when niraparib plus abiraterone acetate and prednisone (AAP) was administered to patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 3 MAGNITUDE trial (NCT03748641).¹

According to longer follow-up from the second prespecified interim analysis of MAGNITUDE, which included 212 patients with mCRPC with homologous recombination repair (HRR) gene alterations who were treated with niraparib plus AAP (BRCA1/2 subgroup, n = 113), with a median follow-up of 24.8 months, niraparib plus AAP significantly improved rPFS at 19.5 months vs 10.9 months with placebo (HR, 0.55; 95% CI, 0.39-0.78; nominal P =.0007). These data were consistent with those reported in the first prespecified interim analysis.

Patients in the HRR altered gene population had a prolonged rPFS (HR, 0.76; 95% CI, 0.60-0.97; nominal P =.0280) at a median follow-up of 26.8 months. There were also no new safety signals observed in the study.

“This is the largest cohort of BRCA harboring mCRPC tumors tested for efficacy of the combination. Patients with tumors harboring HRR mutation were preselected for randomization. Hence, this is the only prospectively validated cohort for targeted therapy. The readouts are clear and supportive of the benefit in this subset that has, as we know, a very grim prognosis. Essentially, rPFS is doubled, hence the prognosis improved. The IPCW analysis for overall survival is also supportive of a trend for improvement, even though it is still early. Of course, this is a key secondary end point,” Eleni Efstathiou, MD, PhD, medical oncologist, and section chief of Genitourinary Medical Oncology at Houston Methodist Cancer Center in Texas, told Targeted Oncology^TM.

The MAGNITUDE study enrolled the largest BRCA1/2 cohort in first-line MCRPC to date. The study included patients with mCRPC who were prospectively identified as HRR-positive, and patients with and without BRCA1/2 alterations were randomly assigned in a 1:1 fashion to receive niraparib at a dose of 200 mg orally plus AAP at 1000 mg/10 mg orally, or placebo plus AAP.

Enrollment in the study was open to patients with mCRPC with metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI, disease in the setting of castrate levels of testosterone 50 ng/dL or less on a gonadotropin releasing hormone analog (GnRHa) or bilateral orchiectomy, and must have been able to continue GnRHa during the study if not surgically castrate.² Additionally, patients were required to have a score of 3 or less on the brief pain inventory-short form question number 3, which was worst pain in last 24 hours. Patients who had received prior taxane for mCRPC or metastatic castration-sensitive prostate cancer were also eligible for enrollment.

In addition to rPFS, the secondary end points assessed at the second prespecified interim analysis were time to symptomatic progression, time to initiation of cytotoxic chemotherapy, and overall survival.¹

Previously reported findings from the MAGNITUDE study showed that patients with HRR alterations, particularly BRCA1/2, derive benefit from treatment with niraparib plus AAP in the first-line.

Findings from the updated analysis showed that in terms of the secondary end points, there were improvements observed in time to symptomatic progression and time to initiation of cytotoxic chemotherapy among patients treated with niraparib plus AAP. Regarding OS, patients in the BRCA1/2 subgroup treated with niraparib plus AAP demonstrated an HR of 0.88 (95% CI, 0.58-1.34; nominal P =.5505). The prespecified inverse probability censoring weighting analysis of OS showed an HR of 0.54 (95% CI, 0.33-0.90; nominal P =.0181). This accounted for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies.

Looking at safety in the HRR-positive population, the most common all grade adverse events in the niraparib plus AAP arm vs placebo plus AAP arm were anemia (50% v 23%), hypertension (33% v 22%), constipation (33% v 16%), and back pain (17% v 22%).

Moreover, these data show the importance of identifying this molecular subset of patients and continue to support the use of niraparib with AAP in patients with mCRPC and select HRR gene alterations, including BRCA1/2.

“We need to continue looking for subsets of patients that will benefit from such combinations, and where the ratio of efficacy to risk is in favor of efficacy, as is the case for HRR-positive populations. There is likely a subset of such patients within the unselected HRR group that would also benefit from such a combination. We should continue researching ways to unveil that subset,” said Efstathiou.

REFERENCES:

Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-782. doi:10.1016/j.annonc.2023.06.009

A study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone for treatment of participants with metastatic prostate cancer (MAGNITUDE). ClinicalTrials.gov. Updated August 18, 2023. Accessed September 25, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03748641