Prof. Dr. Sven Mahler im Interview mit Renate Haidinger, Brustkrebs Deutschland e.V. mit folgenden Themen:
ARIEL3: Rucaparib PARP-Inhibitor Erhaltungstherapie beim Rezidiv des Ovarialkarzinoms
AGO OVAR 2.22 / NOVA Studie: Lebensqualität unter Niraparib Erhaltungstherapie beim Ovarialkarzinom
ICON8: Wöchentliche oder dreiwöchentliche Gabe von Carboplatin und Paclitaxel beim Ovarialkarzinom
LBA40_PR - ARIEL3: A phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC)
Rucaparib has antitumour activity in BRCA-mutant or BRCA wild-type/genomic loss of heterozygosity (LOH) high associated OC. ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC.
Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All responses required CA-125 to be less than the upper limit of normal. Pts were randomised 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested groups: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (BRCA mutant or BRCA wild-type/LOH high); and (3) intent-to-treat population. PFS was also assessed by blinded independent central review (key secondary endpoint) and LOH status in pts with BRCA wild-type OC (exploratory endpoint).
Data are presented for the rucaparib and placebo groups, respectively. ARIEL3 enrolled 564 pts (375 and 189 in each group). PFS data are summarised in the Table. The most common grade 3 or higher treatment-emergent AEs were anaemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 Apr 2017), 13.4% and 1.6% of pts discontinued due to treatment-emergent AEs (excluding disease progression); 1.6% and 1.1% of pts died due to AEs (including disease progression).
|Analysis Population||Rucaparib, n||Placebo, n||PFS by Investigator Review (Primary Endpoint)
||PFS by BICR (Key Secondary Endpoint)
|Hazard Ratio* (95% CI); P Value||Median PFS, mo; P Value†||Hazard Ratio* (95% CI); P Value||Median PFS, mo; P Value†|
|Rucaparib vs Placebo||Rucaparib vs Placebo|
|BRCA mutant||130||66||0.23 (0.16–0.34); P< 0.0001||16.6 vs 5.4; P< 0.0001||0.20 (0.13–0.32); P< 0.0001||26.8 vs 5.4; P< 0.0001|
|HRD (BRCA mutant or BRCA wild type/LOH high)||236||118||0.32 (0.24–0.42); P< 0.0001||13.6 vs 5.4; P< 0.0001||0.34 (0.24–0.47); P< 0.0001||22.9 vs 5.5; P< 0.0001|
|Intent to treat‡||375||189||0.37 (0.30–0.45); P< 0.0001||10.8 vs 5.4; P< 0.0001||0.35 (0.28–0.45); P< 0.0001||13.7 vs 5.4; P< 0.0001|
|BRCA wild type/LOH high||106||52||0.44 (0.29–0.66); P< 0.0001||9.7 vs 5.4; P< 0.0001||0.55 (0.35–0.89); P=0.0135||11.1 vs 5.6; P=0.0114|
|BRCA wild type/LOH low||107||54||0.58 (0.40–0.85); P=0.0049||6.7 vs 5.4; P=0.004||0.47 (0.31–0.71); P=0.0003||8.2 vs 5.3; P=0.0002|
BICR, blinded independent central review. HRD, homologous recombination deficient.Includes pts with BRCA-mutant (130, rucaparib; 66, placebo), BRCA wild-type/genomic LOH high (106, rucaparib; 52, placebo), BRCA wild-type/genomic LOH low (107, rucaparib; 54, placebo), or BRCA wild-type/genomic LOH indeterminate (32, rucaparib; 17, placebo) OC.
Rucaparib significantly improved PFS vs placebo in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Improvement in PFS was observed in non-nested subgroups of pts with BRCA wild-type OC (both LOH high and LOH low).
Clinical trial identification
929O_PR - ICON8: A GCIG phase III randomised trial evaluating weekly dose- dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: Results of primary progression- free survival (PFS) analysis
For several decades, standard first-line chemotherapy for EOC has been carboplatin (C) and paclitaxel (T), administered 3-weekly (q3w). The JGOG3016 trial reported clinically significant lengthening of PFS and overall survival in Japanese women using dose-dense weekly (q1w) T but with increased toxicity. ICON8 is a 3-arm trial, comparing standard q3w CT with dose-dense q1w regimens in a predominantly European patient group.
Eligible women with FIGO stage IcG3- IV EOC were randomised 1:1:1 to Arm 1 (standard) - q3w C AUC5/6 + q3w T 175mg/m2; Arm 2 - q3w C AUC5/6 + q1w T 80mg/m2; Arm 3 - q1w C AUC2 + q1w T 80 mg/m2. Patients entered ICON8 after immediate primary surgery (IPS), or received neo-adjuvant chemotherapy with planned delayed primary surgery (DPS). Primary intention to treat analysis compared arm 2v1 and arm 3v1 using methods for data with non-proportional hazards.
1566 women were randomised Jun 2011-Nov 2014. Median age- 62 years, 72% serous histology, 93% ECOG performance status 0/1. 48% had IPS, 50% planned DPS, 2% inoperable. 72%, 60%, 63% completed 6 cycles protocol-defined treatment in arms 1, 2, 3. Completion rate for 6 cycles platinum was 88% (90%; 89%; 85%). Paclitaxel dose-intensification was achieved (median total dose T (mg/m2)-1011; 1234; 1274). Grade (G) 3/4 toxicity (predominantly uncomplicated low neutrophils) was seen in 42%; 63%; 53% patients. Incidence of G3/4 febrile neutropenia (4%; 6%; 3%) and ≥G2 sensory neuropathy (28%; 25%; 23%) were similar across arms. At Feb 2017, 64% patients had experienced disease progression. No significant increase in PFS was observed with either weekly treatment (log-rank arm 2v1 p = 0.45; arm 3v1 p = 0.56, non-proportionality p = 0.02, restricted mean survival time=24.4; 24.9; 25.3 months in arms 1, 2, 3, median PFS- 17.9; 20.6; 21.1months, HR = 0.92 arm 2v1, HR = 0.94 arm 3v1).
Although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT.
Clinical trial identification
ISRCTN: ISRCTN10356387 EUDRACT: 2010-022209-16 CTA: 2010-022209-16 ENGOT: OV-13 MREC: 11/LO/0043