Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer.

MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and cost‑effectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. NCT03748641 (MAGNITUDE).

Roubaud G ，Attard G ，Boegemann M ，Olmos D ，Trevisan M ，Antoni L ，Pascoe K ，Capone C ，Van Sanden S ，Hashim M ，Palmer S ，Chi K ... -  《-》

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.

Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 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. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Chi KN ，Sandhu S ，Smith MR ，Attard G ，Saad M ，Olmos D ，Castro E ，Roubaud G ，Pereira de Santana Gomes AJ ，Small EJ ，Rathkopf DE ，Gurney H ，Jung W ，Mason GE ，Dibaj S ，Wu D ，Diorio B ，Urtishak K ，Del Corral A ，Francis P ，Kim W ，Efstathiou E ... -  《-》

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Canc

Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plus abiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

De Santis M ，Breijo SM ，Robinson P ，Capone C ，Pascoe K ，Van Sanden S ，Hashim M ，Trevisan M ，Daly C ，Reitsma F ，van Beekhuizen S ，Ruan H ，Heeg B ，Verzoni E ... -  《-》

The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score.

In the COU-AA-302 study (NCT00887198), abiraterone acetate plus prednisone (AAP) significantly improved outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) versus prednisone alone. Baseline clinical parameters predicting that treatment response could help inform clinical decisions were explored. To identify patients who derive the greatest clinical benefit from AAP treatment. A total of 1088 mCRPC patients treated with either AAP or prednisone in the first-line setting in COU-AA-302 were included in this post hoc analysis. Abiraterone acetate1000mg daily versus placebo, both plus prednisone 10mg daily. Univariate and multivariable Cox regression analyses were performed, including clinical and pathological parameters for the primary end points overall survival (OS) and radiographic progression-free survival (rPFS), and secondary study end points. Tumor-associated baseline parameters independently impacting OS were applied to stratify patients according to possible treatment effects. Baseline prostate-specific antigen (PSA), tumor-related pain as assessed by the Brief Pain Inventory-Short Form (BPI-SF), and Gleason score (GS) at primary diagnosis were identified as tumor-associated variables that independently impacted OS. AAP significantly improved outcomes versus prednisone in both group 1 (BPI-SF 0-1 and PSA <80 ng/ml and GS <8; p=0.006; hazard ratio [HR]: 0.61) and group 2 (BPI-SF 2-3 and/or PSA ≥80 ng/ml and/or GS ≥8; p=0.03; HR: 0.84). The differences observed for treatment effects between groups 1 and 2 for OS (HR: 0.61 vs 0.84), rPFS (HR: 0.41 vs 0.59), and time to chemotherapy (HR: 0.64 vs 0.71) were not statistically significant. AAP significantly improved outcomes in mCRPC patients compared with prednisone alone regardless of baseline pain and PSA level, and GS at primary diagnosis with no significant differences between observed treatment effects in groups 1 and 2. Treatment with abiraterone acetate and prednisone (compared with treatment with prednisone only) for metastatic castration-resistant prostate cancer increased survival in all patients in the study regardless of pain, prostate-specific antigen levels at the start of treatment, and Gleason score at primary diagnosis.

Miller K ，Carles J ，Gschwend JE ，Van Poppel H ，Diels J ，Brookman-May SD ... -  《-》

Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer.

Chi KN ，Rathkopf D ，Smith MR ，Efstathiou E ，Attard G ，Olmos D ，Lee JY ，Small EJ ，Pereira de Santana Gomes AJ ，Roubaud G ，Saad M ，Zurawski B ，Sakalo V ，Mason GE ，Francis P ，Wang G ，Wu D ，Diorio B ，Lopez-Gitlitz A ，Sandhu S ，MAGNITUDE Principal Investigators ... -  《-》