Rucaparib versus chemotherapy for treatment of relapsed ovarian cancer with deleterious BRCA1 or BRCA2 mutation (ARIEL4): final results of an international, open-label, randomised, phase 3 trial.
In the ARIEL4 trial of rucaparib versus standard-of-care chemotherapy in patients with relapsed BRCA-mutated ovarian carcinoma, the primary endpoint was met, showing improved investigator-assessed progression-free survival with rucaparib. Here, we present the final overall survival analysis of the trial and other post-progression outcomes.
This open-label, randomised, controlled phase 3 trial was done at 64 hospitals and cancer centres in 12 countries, including Brazil, Canada, Czech Republic, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, the UK, and the USA. Eligible patients were women aged 18 or older with BRCA1 or BRCA2-mutated ovarian carcinoma and had received at least two previous chemotherapy regimens. Patients had to have evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) criteria and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using an interactive response technology and block randomisation (block size of six) and stratified by progression-free interval after the most recent platinum-containing therapy to receive oral rucaparib (600 mg twice daily administered in 28-day cycles) or chemotherapy on the basis of platinum-sensitivity status. In the chemotherapy group, patients with platinum-resistant disease (progression-free interval ≥1 to <6 months) or partially platinum-sensitive disease (progression-free interval ≥6 to <12 months) received weekly paclitaxel (starting dose 60-80 mg/m2 on days 1, 8, and 15). Patients with fully platinum-sensitive disease (progression-free interval ≥12 months) received the investigator's choice of platinum-based chemotherapy (single-agent cisplatin or carboplatin, or platinum-doublet chemotherapy), in 21-day or 28-day cycles. The primary endpoint (previously reported) was investigator-assessed progression-free survival, assessed in the efficacy population (all randomly assigned patients with deleterious BRCA1 or BRCA2 mutations without reversion mutations) and in the intention-to-treat population (all randomly assigned patients). Overall survival was a prespecified secondary endpoint and was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned study treatment. The cutoff date was April 10, 2022. This study is registered with ClinicalTrials.gov, NCT02855944; enrolment is complete and the study is closed.
Between March 1, 2017, and Sept 24, 2020, 349 eligible patients were randomly assigned to receive rucaparib (n=233) or chemotherapy (n=116). 332 (95%) of 349 patients were white and 17 (5%) patients were other or of unknown race. In the chemotherapy group, 80 (69%) of 116 patients crossed over to receive rucaparib. Median follow-up was 41·2 months (IQR 37·8-44·6). At data cutoff for this final analysis (April 10, 2022), 244 (70%) of 349 patients had died: 167 (72%) of 233 in the rucaparib group and 77 (66%) of 116 in the rucaparib group. Median overall survival was 19·4 months (95% CI 15·2-23·6) in the rucaparib group versus 25·4 months (21·4-27·6) in the chemotherapy group (hazard ratio 1·3 [95% CI 1·0-1·7], p=0·047). No new safety signals were observed, including during crossover to rucaparib. The most common grade 3-4 adverse events across treatment groups included anaemia or decreased haemoglobin (reported in 59 [25%] of 232 patients in the rucaparib group and seven [6%] of 113 in the chemotherapy group), and neutropenia or decreased neutrophil count (in 26 [11%] of 232 in the rucaparib group and 16 [14%] of 113 patients in the chemotherapy group). Serious adverse events were reported in 66 (28%) of 232 patients in the rucaparib group and 14 (12%) of 113 patients in the chemotherapy group. Ten treatment-related deaths were reported in the rucaparib group, two of which were linked to judged to be related to rucaparib (cardiac disorder and myelodysplastic syndrome), and one death related to treatment was reported in the chemotherapy group, with no specific cause linked to the treatment.
These data highlight the need for a better understanding of the most appropriate treatment for patients who have progressed on a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, and the optimal sequencing of chemotherapy and PARP inhibitors in advanced ovarian cancer.
Clovis Oncology.
Oza AM
，Lisyanskaya A
，Fedenko A
，de Melo AC
，Shparyk Y
，Rakhmatullina I
，Bondarenko I
，Colombo N
，Svintsitskiy V
，Biela L
，Nechaeva M
，Lorusso D
，Scambia G
，Cibula D
，Póka R
，Oaknin A
，Safra T
，Mackowiak-Matejczyk B
，Ma L
，Thomas D
，Lin KK
，McLachlan K
，Goble S
，Kristeleit R
... -
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Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study.
Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer.
This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up.
After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period.
BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.
Marchetti C
，Fagotti A
，Fruscio R
，Cassani C
，Incorvaia L
，Perri MT
，Sassu CM
，Camnasio CA
，Giudice E
，Minucci A
，Seca M
，Arbustini E
，Vertechy L
，De Bonis M
，Boccia SM
，Giannarelli D
，Salutari V
，Distefano M
，Ferrandina MG
，Nero C
，Musacchio L
，Russo A
，Scambia G
，Lorusso D
... -
《ESMO Open》
DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymeras
With the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need.
The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer.
This study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo.
This is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to BRCA status, and response to platinum-based chemotherapy.
Eligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria.
The primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1.
192 patients.
December 2022.
NCT04239014.
McMullen M
，Karakasis K
，Loembe B
，Dean E
，Parr G
，Oza AM
... -
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PARP inhibitor maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer: a cost-effectiveness analysis.
To determine the cost-effectiveness of olaparib, a PARP inhibitor, as maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer.
Two separate decision analysis models compared the cost of observation versus olaparib maintenance therapy in patients with PS recurrent ovarian cancer, one for patients with a germline BRCA1/2 mutation and one for patients with wild-type BRCA1/2. Patients received six cycles of paclitaxel and carboplatin. Drug costs were estimated using 2014-2015 wholesale acquisition costs. The cost of olaparib was estimated at $13,440 per month. Rate of germline BRCA1/2 mutation was estimated at 20%. Progression-free survival was determined from published data. Incremental cost-effectiveness ratios (ICERs) per progression-free life-year saved (PF-LYS) were calculated. A sensitivity analysis estimated the cost at which olaparib would be cost-effective.
We estimated that there were 5549 patients diagnosed with PS recurrent ovarian cancer in the United States annually. The cost of observation in 1110 patients with a BRCA1/2 mutation was $5.5 million (M) versus $169.2M for maintenance therapy with olaparib. The ICER for olaparib maintenance therapy in patients with a BRCA mutation was $258,864 per PF-LYS. If the cost of olaparib was decreased to $2500 per month, the ICER was $49,584. For the 4439 patients with wild-type BRCA, the cost of maintenance therapy was $444.2M; the ICER was $600,552 per PF-LYS.
For patients with a germline BRCA1/2 mutation, maintenance therapy with olaparib is not cost-effective with an ICER of $258,864 per PF-LYS. To achieve an ICER of less than $50,000, the cost of olaparib should be $2500 or less per month. For wild-type BRCA1/2 patients, maintenance therapy with olaparib is not cost-effective.
Smith HJ
，Walters Haygood CL
，Arend RC
，Leath CA 3rd
，Straughn JM Jr
... -
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ResearchGate
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