Niraparib/Abiraterone/Prednisone Effective With Minimal AEs in BRCA+ mCRPC

Kim Chi, MD

Niraparib (Zejula) with abiraterone acetate (Zytiga) and prednisone maintains good quality of life (QOL) with minimal adverse effects (AEs) for patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC), strengthening the case for niraparib with abiraterone acetate and prednisone (AAP) as a viable treatment option for this specific patient population.

Findings come from the phase 3 MAGNITUDE trial (NCT03748641) which previously showed that patients with mCRPC treated with niraparib plus AAP had improved rates of radiographic progression-free survival (rPFS).

To date, the MAGNITUDE trial enrolled the largest BRCA1/2 cohort in first-line mCRPC. Patients with mCRPC who were prospectively identified as homologous recombination repair (HRR)-positive, and patients with and without BRCA1/2 alterations were enrolled in the study and randomized 1:1 to receive niraparib at a dose of 200 mg orally plus AAP at 1000 mg/10 mg orally, or placebo plus AAP.

Looking at longer follow-up from the second prespecified interim analysis of the MAGNITUDE study, 212 patients with mCRPC with HRR gene alterations were treated with niraparib plus AAP, including 113 patients who made up the BRCA1/2 subgroup. At a median follow-up of 24.8 months, the combination of niraparib with 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). Among those with HRR alterations, prolonged rPFS was observed (HR, 0.76; 95% CI, 0.60-0.97; nominal P =.0280) at a median follow-up of 26.8 months.

Additionally, researchers assessed pain, health-related QOL and AEs, and found that the combination did not worsen pain or QOL vs those treated with placebo. Furthermore, AEs were minimal across both groups.

These data were consistent with those reported in the first prespecified interim analysis, emphasize the importance of identifying this molecular subset of patients, and suggest that this combination may offer a good QOL with minimal AEs for patients with mCRPC.

In an interview with Targeted Oncology^TM, Kim N. Chi, MD, FRCPC, medical oncologist, vice president, chief medical officer, British Columbia Cancer, and professor, Division of Medical Oncology, University of British Columbia, discussed the MAGNITUDE trial results, including patient-reported outcomes (PROs), in patients with BRCA-positive mCRPC.

3D rendered medically accurate illustration of prostate cancer: © SciePro - stock.adobe.com

Targeted Oncology: Can you discuss the significance of the MAGNITUDE trial, including patient-reported outcomes?

Chi: For any clinical trial or new treatment, although it is important that our usual primary end points of radiographic progression-free survival and overall survival are met, we also want to see from a patient perspective how they are doing on the treatments, both from an [adverse] effect point of view [and] a symptom improvement point of view.

How do these insights on patient-reported outcomes differ from traditional clinical endpoints?

Traditional clinical end points tend to be things like response rate, which is a measurement on a CT scan, a [prostate-specific antigen (PSA)] test, which is a lab measurement, or survival, such as how long somebody lives, and these are important. However, they are not necessarily from the patient perspective and from the patient perspective, we want to know how they are doing on it. This is the patient's voice in the treatment.

Beyond overall survival, what specific PRO improvements did patients receiving niraparib, abiraterone acetate, and prednisone experience compared with placebo?

In this trial, we selected patients and what was reported on [was] patients with BRCA alterations or BRCA mutations. BRCA is a gene that, when mutated, can result in defects and homologous recombination repair. These kinds of cancers are very sensitive to PARP inhibitors, such as niraparib. In this study, we evaluated the combination of abiraterone plus niraparib vs abiraterone alone. We did see improvements in radiographic progression-free survival, as well as in subgroup analysis, improvements in overall survival.

In the study, we also looked at patient-reported outcomes, primarily around quality of life, as well as pain, and specifically looked at questions around [adverse] effects. What we found is that overall quality of life was maintained. Despite the improvements and the more intensified therapy with the PARP inhibitor, quality of life was maintained, which is important. So the extra [adverse] effects from treatment were not impacting their quality of life. We did see a trend to delayed pain progression, which is also important as a symptom, and then thirdly, what we saw is that the [adverse] effect bother was pretty minimal. Altogether, we see patient benefits in terms of radiographic progression-free survival trends to overall survival trends to pain progression improvements. However, it was not at a detriment of quality of life or [adverse] effect bother.

Do you think this could kind of inform personalized treatment decisions in future patients?

For sure. I think when I am approaching my patients about getting this kind of treatment, and it is an approved treatment for patients with BRCA alterations and metastatic CRPC, I can let them know the full picture of the benefits, as well as the risks of treatment. It helps inform them that and reassure them that this kind of treatment will not have a big impact on their overall quality of life.

Were there any kinds of downsides or challenges that were seen in this trial?

While for any treatment there are [adverse] effects, and certainly PARP inhibitors, although reasonably well-tolerated, do have their [adverse] effects. That includes predominantly myelosuppression, in particular, in the form of anemia, as well as fatigue, and as well as some nausea. But overall, the [adverse] effects were mild and manageable.

How do the findings from the MAGNITUDE study translate into everyday practice? What practical tools or resources can be used to monitor and address these patient-reported outcomes?

I think this reinforces the need to identify patients with BRCA alterations and HRR mutations in general. It emphasizes the recommendations that for all patients with metastatic prostate cancer, we need to be doing genetic testing to understand if their cancers have these. There are many implications to this, so hereditary cancer implications, prognostic implications, but as well, treatment implications, because these patients can be treated with PARP inhibitors. I think this is a standard of care that we should be moving forward with.

More and more, we are seeing the ability to incorporate patient-reported outcomes into our everyday practice. This is becoming a standard across many organizations and institutions. Certainly, I encourage its use. We know that monitoring a patient’s quality of life can really improve their outcomes.

REFERENCES:

1. 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

2. Rathkopf DE, Roubaud G, Chi KN, et al. Patient-reported outcomes (PRO) in patients (pts) with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC) receiving niraparib (NIRA) with abiraterone acetate and prednisone (AAP): Results from MAGNITUDE study. J Clin Oncol. 2024;42(Suppl 4):105. doi:10.1200/JCO.2024.42.4_suppl.105