Epithelial ovarian cancer presents in most participants at an advanced stage when curative
surgery is not possible because of extensive pelvic, abdominal or distant metastases.
Immediate or delayed surgery combined with platinum-based chemotherapy are the standards of
care but even with complete surgical cytoreductive techniques and the prescription of
combination platinum-based chemotherapy, the 5 year survival rate remains approximately 35%.
Approximately 50% of ovarian cancers harbour defects in HR. Defects in the pathway can arise
as a result of genomic or epigenetic events in any one of up to 33 genes.
Phase I and II clinical trials with the PARPi, olaparib, have shown promising results in BRCA
mutated (BRCAm) recurrent EOC and in a proportion of HGSOC participants with wild type
germline BRCA (BRCA wt). Additionally the favourable toxicity profile of olaparib has
prompted the long-term use of PARPi as a maintenance strategy. The results of a randomized
placebo-controlled phase II clinical trial of olaparib maintenance therapy showed an
improvement in progression free survival (PFS) and time to progression in participants with
recurrent platinum-sensitive HGSOC6. Recent data have confirmed that the increase in median
PFS is most marked in BRCAm participants who received olaparib as maintenance treatment
compared with the BRCAm participants who received placebo treatment (11.2 vs 4.3 months
respectively; HR, 0.18; 95% CI, 0.11-0.31; p<0.00001). These studies were performed with the
original capsule formulation of olaparib at a dose of 400mg bd.
Rationale for this study The improvement in PFS with maintenance olaparib in participants
with germline BRCA-mutation (g-BRCAm), although particularly striking, has not translated
into improved overall survival, presumably because subsequent salvage therapy obscures this
effect. Emerging data indicate that a significant proportion of BRCAm HGSOC participants
retain sensitivity to platinum agents or other chemotherapies following progression on
olaparib. Thus it is appropriate to offer further platinum-containing therapy to participants
whose disease progresses more than 6 months after previous platinum therapy. In those whose
disease benefits from further platinum chemotherapy, a further course of olaparib might
consolidate the gains from the first course of olaparib, improving PFS to the point that OS
is increased as well. However, to date no trial has tested the feasibility of successive
treatments with 2 or more courses of maintenance olaparib and this issue will be addressed
here, in participant who harbour a germline BRCA defect and whose disease has recurred and
which is at least stabilised by subsequent platinum-based chemotherapy.
Functional testing remains the gold standard test for HR status and has greater predictive
accuracy than non-functional tests. The Rad51 functional assay involves the recognition of
completion of HR by the formation of Rad51 foci in viable cells that have undergone DNA
damage, recognised by γH2AX focus formation. The assay is robust and reproducible but
requires viable cells derived from either participant ascites or solid tumour deposits.
Inclusion Criteria:
1. Progressive, measureable high grade serous or endometrioid ovarian cancer, fallopian
tube or primary peritoneal cancer
- Participants who have not been treated with PARP inhibitor previously will be
treated with two maintenance courses of olaparib.
- Participants, who have received one course of maintenance olaparib before entry
to the trial, will only receive one further course of treatment.
2. Aged 18 or over
3. Measureable disease by RECIST 1.1
4. ECOG performance status 0-2 and life expectancy of over 12 weeks
5. Adequate haematological function: Hb ≥ 10.0 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets
≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or
APPT ratio <1.4
6. Adequate liver function: bilirubin ≤1.5 x ULN, Transaminases (ALT and AST) ≤2.5x ULN
unless liver metastases are present in which case they must be ≤ 5x ULN
7. Adequate renal function defined as GFR ≥ 51ml/min
8. Written, informed consent that includes genetic research on tissue derived from
biopsies.
9. Pathogenic germline BRCA-1 or -2 gene mutation
10. Ability to swallow oral medication (tablets).
Exclusion Criteria:
1. Concurrent medical illness that would impact on compliance with the protocol including
MDS/ AML
2. Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain
metastases is not required.
3. Known positivity for Hep B, Hep C or HIV.
4. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome
5. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is 2 weeks.
6. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
weeks for other agents.
7. Another cancer, which has been active within the previous 5 years, with the exception
of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or
squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy.
8. Female participants who are able to become pregnant (or are already pregnant or
lactating) unless the following apply: Those who have a negative serum or urine
pregnancy test before enrolment and agree to use two highly effective forms of
contraception (oral, injected or implanted hormonal contraception and condom, have an
intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four
weeks before entering the trial, during the trial and for one month afterwards are
considered eligible. Alternatively if the participant can abstain from sexual
intercourse for the same interval, then they are eligible to participate.
9. Participants who are planning to receive maintenance bevacizumab.
10. Participants will be excluded if the side effects of previous treatments have not
resolved to grade I or less, with the exception of alopecia or grade 2 neurotoxicity
that is considered related to cytotoxic chemotherapy.
11. Radiotherapy, surgery or tumour embolization within 28 days before the cycle 1 day 1
of the platinum-containing chemotherapy.
12. Additional concurrent anti-cancer therapy.
13. Causes of malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma is not
permitted.
14. Participants who have contra-indications to VEGF inhibitors will not be eligible to
receive cediranib (second treatment). These contra-indications include concurrent or
past history of malignant fistula, uncontrolled hypertension, recent arterial
thrombosis (cerebrovascular accident or myocardial infarction) within the past 6
months, participants who are at risk of bowel perforation, proteinuria greater than
2g/24 hours or a past history of VEGF inhibitor-associated reversible posterior
leukoencephalopathy.
15. Any participant that is participating in another interventional clinical trial within
30 days or 5-lives prior to signing of consent. Participation in an observational
trial would be acceptable.
