A retrospective analysis of Phase II data has indicated that the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib may be effective as a treatment for advanced ovarian cancer patients with BRCA1/2 mutations. AstraZeneca is taking a risk by moving olaparib into a Phase III pivotal trial having previously discontinued its development in 2011. The retrospective analysis did not show a significant overall survival (OS) advantage, and so AstraZeneca is hoping that a large progression-free survival (PFS) benefit in the planned pivotal study will be sufficient to gain regulatory approval.
On Saturday 1 June at the 49th American Society of Clinical Oncology (ASCO) annual meeting, Dr Jonathan Ledermann presented a retrospective analysis of Phase II trial data of the PARP inhibitor olaparib in advanced serous platinum-sensitive ovarian cancer. Dr Ledermann showed that stratification of data by patients’ BRCA1/2 mutation status revealed olaparib is most likely to benefit patients with deleterious BRCA1/2 mutations (BRCAm).
PARP inhibitors block the activity of PARP, an enzyme that plays an essential role in DNA repair mechanisms. PARP inhibitors act by directly blocking enzymatic activity, or by causing PARP to accumulate on DNA (PARP trapping), which results in DNA replication inhibition and cell death. Tumor cells with BRCA1/2 gene mutations are dependent on PARP for DNA damage repair, and PARP inhibition selectively kills BRCA1- or BRCA2-deficient cells. As DNA repair is inhibited by PARP inhibitors, they are often sequenced after a cytotoxic chemotherapy which works by damaging DNA.
BRCA1/2 encode proteins that are required for DNA damage repair. Inherited mutations in these genes have been linked to a predisposition for development of breast and ovarian cancers. In the US, it has been estimated that inherited BRCA1 and BRCA2 mutations account for 5–10% of breast cancers and 10–15% of ovarian cancers among white women. Up to 50% of women with high-grade serous ovarian cancer could be deficient in homologous recombination (a process involved in DNA repair) due to inherited BRCA1/2 mutations, epigenetic inactivation of BRCA1/2, or other defects independent of BRCA1/2.
Study 19 was a randomized, double-blind, placebo-controlled Phase II study that assessed the efficacy and safety of olaparib as a maintenance monotherapy in women with advanced platinum-sensitive relapsed serous ovarian cancer. Patients in the study were required to have already been treated with two different platinum-based chemotherapies and displayed evidence of an objective and stable maintained response on their last treatment. Patients were randomized to receive either olaparib 400mg twice daily, or placebo twice daily.
Retrospective analysis of Study 19 demonstrated that olaparib may be an effective maintenance therapy for a subset of ovarian cancer patients. Dr Ledermann explained that after stratifying patients by BRCA1/2 mutation status, it was clear that BRCAm patients were more likely to benefit from olaparib maintenance monotherapy. Olaparib treatment was shown to confer an 82% (p<0.00001) reduction in risk of disease progression or death in BRCAm patients. This translated to a median PFS of 11.2 months in patients treated with olaparib compared with 4.3 months in patients treated with placebo.
Dr Ledermann also discussed a “strong trend” for olaparib in conferring a numerical median OS advantage compared with placebo in BRCAm patients (34.9 months versus 31.9 months), although this was not statistically significant (p<0.208). In addition, data for an exploratory secondary endpoint, PFS2, were also disclosed. PFS2 describes the time between initiation of olaparib treatment and disease progression on a therapy given subsequently to olaparib (the time by which cancer has progressed twice on two different therapies). The median PFS2 of BRCAm patients was significantly higher in the olaparib group than in the placebo group (23.8 months versus 15.3 months [p<0.0003]).
AstraZeneca’s U-turn on olaparib development is a sign that it has recognized that PARP inhibitors are likely to be effective only in very carefully selected patients. Those most likely to benefit are BRCAm patients with platinum-sensitive disease. AstraZeneca had previously announced in 2011 that it was discontinuing development of olaparib in ovarian cancer due to a poor outcome in Study 19. However, this retrospective analysis of the data from Study 19 identified that BRCAm patients were those most likely to benefit from treatment with olaparib, and AstraZeneca has now announced the progression of olaparib into Phase III development. The planned Phase III pivotal study is designed to assess olaparib’s efficacy as a maintenance therapy for patients who have previously received treatment with platinum-based chemotherapy. Crucially, the inclusion criteria of the trial state that patients must have deleterious or suspected deleterious BRCA1/2 mutations.
When questioned about the lack of significant OS benefit, Dr Ledermann voiced skepticism about whether the planned Phase III study could provide these data. He cited the PFS2 value as a more appropriate measure of clinical benefit in recurrent ovarian cancer patients: “I think that the PFS2 value is in some way a surrogate for OS, and is a measure of the additional clinical benefit beyond first progression.”
Expanding on this, Dr Lederman stated that it is difficult to show an OS benefit in refractory ovarian cancer patients as they may go on to receive other post-progression therapies and can live for many more years.
AstraZeneca is investigating olaparib as a maintenance therapy, with the expectation that a robust improvement in PFS will be enough for it to gain approval. As a maintenance therapy, advanced platinum-sensitive ovarian cancer patients will receive olaparib after previously demonstrating remission on a cycle of platinum-based chemotherapy such as carboplatin. After disease progression on olaparib, patients could then potentially be switched back to platinum-based therapy. Measuring OS in this setting is complicated, as patients will often receive two or more different drugs over their treatment periods. Taking this into account, it is understandable that AstraZeneca has made PFS the primary endpoint for the pivotal study, and it is probable that a significant PFS benefit would be sufficient for olaparib’s approval.
