Longer follow-up from the second prespecified interim analysis of the MAGNITUDE study that enroled the largest BRCA1/2 cohort in first-line setting of patients with metastatic castration-resistant prostate cancer (mCRPC) to date, demonstrate improved radiographic progression-free survival (rPFS), time to symptomatic progression, and time to initiation of cytotoxic chemotherapy with niraparib plus abiraterone acetate and prednisone in patients with BRCA1/2-altered mCRPC.
The results reinforce the need for genomic testing for patients with mCRPC in the first-line setting to identify those patients who would potentially derive optimal benefit in response to treatment with PARP inhibitors according to Prof. Kim N. Chi of the University of British Columbia, BC Cancer-Vancouver Center in Vancouver, BC, Canada, and colleagues who published the findings on 1 July 2023 in the Annals of Oncology.
Up to 30% of patients with mCRPC harbour alterations in genes associated with DNA damage repair, including homologous recombination repair (HRR) genes, which are associated with poor clinical outcomes and earlier resistance to commonly used systemic therapies. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR mutations, with the greatest clinical benefit for BRCA1/2 mutation carriers. Niraparib is being studied in patients with mCRPC in the ongoing phase III MAGNITUDE study.
In MAGNITUDE, of 423 enroled patients with HRR-positive mCRPC, 225 (53.2%) had BRCA1/2 positive tumour, making it the largest cohort of BRCA1/2-positive mCRPC studied in the first-line setting to date. Furthermore, MAGNITUDE was designed to be representative of patients with mCRPC seen in clinical practice for first-line treatment by allowing patients to have recently received next-generation androgen receptor inhibitors for metastatic castration-sensitive prostate cancer and non-metastatic CRPC, as well as permitting up to 4 months of abiraterone acetate with prednisone for first-line mCRPC before enrolment to allow for time to carry out genomic analyses and obtain results.
The authors wrote in the background that the first interim analysis of MAGNITUDE, with a median duration of follow-up in the HRR-positive cohort of 18.6 months, demonstrated that niraparib plus abiraterone acetate and prednisone significantly improved the primary endpoint of rPFS in patients with mCRPC and HRR gene alterations. A preplanned futility analysis in patients with mCRPC without HRR gene alterations showed no benefit for the combination of niraparib plus abiraterone acetate and prednisone. In the latest article published in the Annals of Oncology, the study team report updated results from the second interim analysis with a focus on the preplanned subgroup analysis of patients with BRCA1/2 alterations.
Patients with mCRPC were prospectively identified for having HRR-positive mCRPC with or without BRCA1/2 alterations and randomised 1:1 to niraparib 200 mg orally plus abiraterone acetate 1000 mg and prednisone 10 mg orally or placebo plus abiraterone acetate and prednisone. At second interim analysis, secondary endpoints time to symptomatic progression, time to initiation of cytotoxic chemotherapy, and overall survival (OS) were assessed.
Overall, 212 patients with HRR-positive mCRPC received niraparib plus abiraterone acetate and prednisone of whom 113 made BRCA1/2 subgroup. At second interim analysis with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus abiraterone acetate and prednisone significantly prolonged rPFS per blinded independent central review with median rPFS of 19.5 versus 10.9 months (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.39-0.78; nominal p = 0.0007) consistent with the first prespecified interim analysis. At median follow-up 26.8 months, rPFS was also prolonged in the total HRR-positive population (HR 0.76, 95% CI 0.60-0.97; nominal p = 0.0280].
Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus abiraterone acetate and prednisone. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus abiraterone acetate and prednisone demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal p = 0.5505). Prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of PARP inhibitors and other life-prolonging treatments, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal p = 0.0181).
The authors concluded that the results from second prespecified interim analysis of MAGNITUDE study confirm that after a median follow-up of 24.8 months in patients with BRCA1/2 alterations, the combination of niraparib plus abiraterone acetate and prednisone continued to improve rPFS, demonstrating a 45% reduction in the risk of radiographic progression or death, which corresponded to an extension of the median rPFS by 8.6 months over placebo plus abiraterone acetate and prednisone, yielding a median rPFS of more than 1.5 years.
The clinical relevance of the benefit in rPFS was supported by delays in time to symptomatic progression and time to initiation of cytotoxic chemotherapy for the BRCA1/2 subgroup and the total HRR-positive population treated with niraparib plus abiraterone acetate and prednisone versus placebo plus abiraterone acetate and prednisone. While OS data are still maturing and a final analysis of the MAGNITUDE study is planned, there was a non-statistically significant improvement in OS observed in the stratified analysis for the BRCA1/2 subgroup, with a more robust effect observed in the analysis that accounted for imbalances in baseline characteristics.
Other PARP inhibitors, olaparib and talazoparib, have shown efficacy in combination with abiraterone acetate and prednisone and enzalutamide in studies of patients with mCRPC who were not preselected to have an HRR gene alteration (‘all-comers’ population), but similarly to niraparib, the greatest benefits have been among patients with ≥1 alteration in BRCA1/2. In an accompanied editorial article, Dr. Ugo De Giorgi of the Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’ in Meldola, Italy, and colleagues wrote if we compare the MAGNITUDE, PROpel, and TALAPRO-2 studies, BRCA status should be considered as the essential predictive biomarker of clinical outcome due to a strong correlation with rPFS/OS improvement.
According to the editorialists, the OS data from the MAGNITUDE study should be interpreted in the light of post-study treatments, as up to 20% of patients in the control group received PARP inhibitor as subsequent treatment. In a network analysis of the PROfound and CARD studies in patients with mCRPC who progressed on prior androgen receptor signalling inhibitor (ARSI), OS was not significantly different between olaparib and cabazitaxel. Despite the indirect nature of this analysis and the differences among the two studies, the impact of PARP inhibitor in subsequent lines could be inferior to the standard of care.
The editorialists also wrote that the predictive role of HRR for PARP inhibition should be re-examined, since the survival benefit seems to be mainly driven by BRCA mutations. The US Food and Drug Administration has recently limited the approval of the olaparib and abiraterone combination in the subgroup of patients with BRCA1/2–positive disease, based on the results of a subgroup analysis of the PROpel study, which indicated that the rPFS/OS improvement in the intention-to-treat population was attributable only to patients with BRCA1/2–positive tumours.
When BRCA mutations are undetectable on both tissue and plasma analyses, adding PARP inhibitor to ARSI does not translate to any survival advantage. Results of similar subgroup analyses on TALAPRO-2 study with adequate follow-up are warranted to provide better comparisons among phase III studies in first-line mCRPC to confirm that the efficacy is definitely attributable to the BRCA gene and/or other HRR gene mutations.
In MAGNITUDE, another aspect to be considered is safety, given the higher percentage of treatment-related adverse events in the combination arm (77.8% versus 57.3% in the placebo arm) and dose modifications. The right balance between safety and efficacy would be crucial to maximise overall patient benefit according to the editorialists.
BRCA1/2-positive status has been recently associated with a significantly shorter time to castration resistance. Ongoing TALAPRO-3 and AMPLITUDE studies conducted in patients with metastatic hormono-sensitive prostate cancer treated with ARSI with or without PARP inhibitor in the treatment-naïve or post-docetaxel maintenance settings may better define the optimal clinical setting for PARP inhibition in metastatic prostate cancer.
The findings from the MAGNITUDE second interim analysis were previously presented in part at the ASCO 2023 Genitourinary Cancers Symposium (16-18 February, San Francisco, CA, US).
This work was supported by Janssen Research & Development, LLC.
