The following full text is a publisher's version.For additional information about this publication click this link. https://hdl.handle.net/2066/229509Please be advised that this information was generated on 2023-04-03 and may be subject to change.T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 383;24 nejm.org

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Background Poor-prognosis germ-cell tumours (GCT) are associated with only a 50% cure rate. Our hypothesis was that treatment intensification based on an early tumour marker decline will improve progression-free survival (PFS). Methods In this phase III, multicentre, international trial (NCT00104676 ; EU-20502), after patients with poor-prognosis GCT defined according to the International Germ-Cell Cancer Consensus Group (IGCCCG) had received one cycle of cisplatin (20 mg/m2/day × 5 days), etoposide (100 mg/m2/day × 5 days), and bleomycin (30 mg/week) (BEP), AFP and hCG were assessed between day 18 and 21: 1) patients with a favourable decline continued BEP (Fav-BEP); 2) patients with an unfavourable decline were randomised to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel (175 mg/ m2 day 1)-BEP plus oxaliplatin (130 mg/ m2 day 10) (2 cycles), followed by cisplatin (100 mg/ m2 day 1), ifosfamide (2 g/ m2 on days 10, 12, 14 + mesna), and bleomycin (25 units/day, by continuous infusion × 5 days on day 10 to 14) (2 cycles), with G-CSF support. Centrally blocked randomisation stratified by centre was used. The primary endpoint was PFS and the efficacy analysis was conducted on an intention-to-treat basis i.e. it included all randomised patients. The planned trial accrual was completed in May 2012 and follow-up is ongoing. Results 263 patients were enrolled and 203 had an unfavourable tumour marker decline (randomised: 105 Unfav-dose-dense arm, 98 Unfav-BEP arm). The 3-year PFS rate was 59% [95% Confidence Interval (CI): 49–68] in the Unfav-dose-dense arm versus 48% [95% CI: 38–59] in the Unfav-BEP arm (p=0.05; HR: 0.66 [95% CI: 0.44–1.00]). The 3-year PFS rate was 70% [95% CI: 57%–81%] for patients in the Fav-BEP arm (p=0.01 for PFS compared with the Unfav-BEP arm). More grade 3–4 neurotoxicity (7 [7%] vs 1 [1%]) and greater haematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + a stem-cell transplant were required in 6 [6%] in the Unfav-dose-dense arm and 16 [16%] patients in the Unfav-BEP arm (p=0.015). Conclusion Personalising treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor-prognosis GCT and an unfavourable tumour marker decline.

12 Background: Approximately 20% of mCRPC has alterations in genes associated with HRR and is responsive to PARP inhibitors (PARPi) such as NIRA. Combined PARPi with androgen receptor pathway targeting may also benefit unselected mCRPC. MAGNITUDE assessed whether adding NIRA to AAP improves outcomes in pts with mCRPC with or without alterations in HRR associated genes. Methods: MAGNITUDE (NCT03748641) is a randomized, double-blind phase 3 study. In eligible mCRPC pts, ≤4 mos of prior AAP for mCRPC was allowed. Pts with (HRR biomarker [BM]+; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM-) were randomized 1:1 to receive NIRA 200 mg once daily + AAP or placebo (PBO) + AAP. Primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in the BRCA1/2 group followed by all HRR BM+ pts. Secondary endpoints were time to initiation of cytotoxic chemotherapy (TTCC), time to symptomatic progression (TTSP) and overall survival (OS). Other endpoints included time to PSA progression (TTPP) and objective response rate (ORR). Results: 423 HRR BM+ pts were randomized to NIRA + AAP (n = 212) or PBO + AAP (n = 211). Median age was 69, 23% had prior AAP, 21% had visceral metastases, and 53% had BRCA1/2 mutations. Median follow-up was 18.6 mos. NIRA + AAP significantly improved rPFS by BICR in the BRCA1/2 subgroup and in all HRR BM+ pts, reducing the risk of progression or death by 47% (16.6 vs 10.9 mo) and 27% (16.5 vs 13.7 mo) respectively (Table), vs PBO + AAP. Investigator assessed rPFS was consistent with BICR. NIRA + AAP delayed TTCC, TTSP, and TTPP and improved ORR in HRR BM+ pts (Table). First interim analysis of OS is immature. The preplanned futility analysis in 233 HRR BM- pts showed no benefit of adding NIRA to AAP in the prespecified composite endpoint (first of PSA progression or rPFS; HR, 1.09; 95% CI, 0.75-1.57). No new safety signals were seen. In HRR BM+ pts, 67% and 46.4% had grade 3/4 AEs and 9% and 3.8% discontinued treatment in the NIRA + AAP and PBO + AAP arms, respectively. There were no clinically significant differences in overall quality of life (FACT-P). Conclusions: NIRA + AAP improves rPFS and other clinically relevant outcomes in pts with mCRPC and alterations in HRR associated genes. There was no evidence of benefit with the addition of NIRA to AAP in HRR BM- pts with mCRPC. Clinical trial information: NCT03748641. [Table: see text]