(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16th and 18th was host to a Prostate Cancer Rapid Abstract Session. Dr. Eleni Efstathiou presented the second interim analysis of MAGNITUDE, which evaluates the combination of niraparib and abiraterone acetate/prednisone in patients with metastatic castrate-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Dr. Efstathiou began by highlighting that patients with mCRPC and HRR gene alterations, especially BRCA mutations, have poor outcomes.1 In the Phase 3 MAGNITUDE study initially presented at last year’s ASCO GU symposium, the futility analysis demonstrated that patients without HRR gene alterations (i.e. HRR-) had no improvement in outcomes from the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor plus abiraterone acetate with prednisone (APP). MAGNITUDE explored the largest cohort of BRCA1/2 positive patients in mCRPC (n=225), with blinded independent central review-assessed radiographic progression-free survival (rPFS) as the primary endpoint to assess the benefit of using niraparib + AAP versus placebo + AAP in patients with BRCA mutations. It is important to note that the MAGNITUDE patient population is representative of patients treated in practice today, as it allowed standard of care, next-generation androgen receptor inhibitors in metastatic castration-sensitive prostate cancer and nmCRPC, as well as up to 4 months of AAP, for first line mCRPC prior to enrollment.
Again, as noted in the figure above, given the futility of combination niraparib/AAP in the HRR- cohort, only HRR+ outcomes were subsequently evaluated. In this update, Dr. Efstathiou presented the update outcomes for the BRCA subgroup only.
As of the 2nd interim analysis cutoff of June 17, 2022, the overall median follow up was 26.8 months, with median treatment duration of 17.9 months for niraparib/AAP versus 15.2 months for placebo/AAP. At this cutoff, 34.9% of patients receiving niraparib/AAP remained on therapy, with 27% continuing on placebo/AAP. Treatments arms were generally well-balanced between the two HRR+ arms, with numerically more patients with ECOG PS 1 (38.7% versus 30.8%) and visceral metastases (24.1% versus 18.5%) in the niraparib/AAP arm. BRCA1/2 mutations were present in just over half of HRR+ patients (53%).
In the BRCA subgroup, the combination of niraparib/AAP was associated with a significant, clinically meaningful improvement in centrally reviewed rPFS (median 19.5 versus 10.9 months; HR: 0.55, 95% CI: 0.39 – 0.78, p=0.0007). Similar benefit was seen with using investigator-assessed rPFS (HR: 0.46, 95% CI: 0.32 – 0.67).
Time to symptomatic progression in the BRCA subgroup was significantly prolonged in the combination arm of niraparib/AAP (median not reached versus 23.6 months; HR: 0.54, 95% CI: 0.35 – 0.85, p=0.0071).
The combination of niraparib/AAP was also shown to significantly prolong time to initiation of cytotoxic chemotherapy in the BRCA subgroup (median not reached versus 27.3 months; HR: 0.56, 95% CI: 0.35 – 0.90, p=0.0152). Substantially more BRCA patients in the placebo/AAP arm (n=22) received subsequent PARP inhibitors with or without chemo treatment relative to the niraparib/AAP arm (1).
With regards to overall survival in the BRCA subgroup, this outcome was analyzed using two methods:
- In the inverse probability censoring weighted (IPCW) analysis of OS, the combination of niraparib/AAP was associated with a 46% reduction in the hazard of overall survival (HR: 0.54, 95% CI: 0.33 – 0.90)
- The OS stratified analysis demonstrated a 12% hazard reduction with a HR of 0.88 (95% CI: 0.58 – 1.34)
In the BRCA subgroup, patients treated with niraparib/AAP experienced:
- Delayed time to worst pain intensity (HR: 0.70, 95% CI: 0.44 – 1.12, nominal p=0.1338)
- Delayed pain interference (HR: 0.67, 95% CI: 0.40 – 1.12, nominal p=0.1275)
The safety profile in all HRR+ patients for niraparib/AAP at the 2nd interim analysis was consistent with that seen in the 1st interim analysis, with no new safety signals observed:
- The most common AEs for niraparib/AAP, regardless of causality, were anemia (50% versus 22.7%, respectively), hypertension (33% versus 22.3%), and constipation (33% versus 15.6%).
Dr. Efstathiou concluded her presentation as follows:
- It appears that patients with mCRPC harboring BRCA alterations have particularly poor outcomes with AAP alone, with a median rPFS of 10.9 months, relative to the historically observed rPFS of 16.5 months in an unselected population treated with AAP alone (COU-AA-302).
- With a longer median follow-up of 26.8 months, MAGNITUDE confirms the benefit of niraparib/AAP combination, with a 45% reduction in the risk of progression or death and extension of the median rPFS to >1.5 years at the 2nd interim analysis, compared with placebo/AAP
- As niraparib/AAP combination improves rPFS, time to symptomatic progression, and time to cytotoxic chemotherapy, with a trend toward improvement in OS also observed, the MAGNITUDE 2nd interim analysis results continue to support genomic testing in mCRPC as well as the use of niraparib/AAP in HRR+ mCRPC patients, particularly those with BRCA gene alterations.
Presented by: Eleni Efstathiou, MD, PhD, Section Chief of Genitourinary Medical Oncology, Houston Methodist Cancer Center, Houston, TX
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
- Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228.
- Ryan CJ, et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med. 2013;368:138-148.