Ovarian cancer represents a significant unmet need in gynaecological cancers as the absence of well-defined screening programmes and inconsistent initial symptoms lead to late diagnosis in the majority of patients. Considered largely incurable, ovarian cancer typically relapses within 3 years in 80% of women, with subsequent recurrences arising sooner each time as resistance to chemotherapy develops.
Despite significant therapeutic achievements with molecular targeted agents in the last five years, Dr Domenica Lorusso, Fondazione Policlinico Gemelli IRCCS and Catholic University of Sacred Heart in Rome, Scientific Co-Chair of the ESMO Gynaecological Cancers Virtual Congress 2021, argues that saving more women in the future will require better tools to select patients for personalised treatment and identify those in whom the disease could be prevented altogether.
Four clinical trials demonstrated significant benefits of poly ADP ribose polymerase (PARP) inhibitors in some ovarian cancer patients. How has this research changed their prognosis?
Research to date has focused on extending the time interval before recurrence. Before PARP inhibitors, the only maintenance treatment was the anti-angiogenesis agent bevacizumab, which is associated with an approximately four-month increase in progression-free survival (PFS) when combined with carboplatin-paclitaxel chemotherapy (J Clin Oncol. 2010;28(18_suppl):LBA1). Initially developed in the recurrent setting, PARP inhibitors were shown to prolong PFS by about 10 months (Lancet 2017 October 28;390(10106):1949-1961) in women with BRCA-mutated cancer, which represents up to 30% of serous ovarian tumours, the most common type of ovarian cancer. In the recurrent setting similar results were achieved in an additional 20% of patients who, in the absence of a BRCA mutation, still have homologous recombination deficiency (HRD) creating an analogous synthetic lethality context in their tumour, and in patients without any defect in DNA repair.
In 2018, the SOLO1 trial of olaparib as first-line maintenance treatment after first-line chemotherapy (N Engl J Med. 2018 December 27;379:2495-2505) was the first to report an unprecedented 70% reduction in the risk of recurrence at three years from randomisation for newly diagnosed BRCA-mutated patients. Even more strikingly, follow-up data (Ann Oncol. 2020 September 1;31(suppl_4):S613) suggested a long-term benefit in that at five years, almost 50% of patients receiving olaparib were free from disease progression compared to just one in five subjects in the placebo group. Two other trials, PRIMA and PAOLA 1, reported a significant benefit in PFS of maintenance parp, alone or in combination with bevacizumab in HRD (PAOLA 1 trial) and all comers (PRIMA trial) high grade serous and endometrioid, newly diagnosed, stage III-IV ovarian cancer patients. The clear message from all these trials is that PARP inhibitors should be used as first-line maintenance therapy, and that we may do so regardless of patients’ BRCA or HR-deficiency (HRD) status, because we also observed a 32% reduction in the risk of recurrence among HR-proficient patients with niraparib in the PRIMA trial (N Engl J Med. 2019 December 19;381:2391-2402).
With four PARP inhibitors now approved to treat advanced ovarian cancer, what challenges still need to be overcome before they become the standard of care?
The previous studies left a number of questions unanswered, such as whether PARP inhibitors should be used alone or in combination with bevacizumab and whether they are really the best treatment for HR-proficient patients. Another significant obstacle to the use of PARP inhibitors in the clinic is deciding who to give them to: the combination of olaparib with bevacizumab has been approved only in HRD patients, but we currently have no reimbursed tests with which to identify them. The only commercially available test to have been validated in clinical trials relies on next-generation sequencing, which has a cost that not all national health systems can support. Efforts are underway to develop an alternative that is both easily reproducible and affordable.
There are also troubling reports that PARP treatment reduces the efficacy of subsequent platinum-based chemotherapy (ESMO Open 2021 June 1;6(3):100135). This is not surprising, because we know that one of the mechanisms of resistance to PARP inhibition is the reversion of BRCA mutations, which also conditions tumour response to platinum. The immediate implication is that we need to re-evaluate the biology of disease at the time of recurrence with a new biopsy to find out whether restored HR proficiency through reverse mutations should lead us to offer an alternative second-line therapy. The task for clinical research in the medium term will be to better understand how treatment should be sequenced, what medicines should be offered after PARP inhibition and how to overcome this mechanism of resistance in order to possibly offer a PARP after PARP strategy.
Do you see a potential for immunotherapy to complement existing treatments?
The trial results so far are quite disappointing. Used in combination with chemotherapy as first-line treatment in the JAVELIN Ovarian 100 study (Gyn Oncol. 2020 October 1;159(suppl_1):13-14), avelumab failed to demonstrate a benefit beyond that of chemo alone. Given together with bevacizumab and chemo in the IMagyn trial (J Clin Oncol. 2021 April 23), atezolizumab equally failed to show an additional benefit over and above the standard of care.
This may be due in part to the lack of predictive biomarkers of response for patient enrolment, as a post-hoc hypothesis-generating analysis of the IMagyn trial did suggest a benefit for a sub-group of patients with high expression of PD-L1. There is also mounting evidence that immunotherapy could have a role in treating the clear-cell ovarian cancer subtype (Ann Oncol. 2020 September 1;31(suppl_4):s627). Patient selection therefore needs to be improved if we are to continue exploring immunotherapy, and we also need to identify the most appropriate combination for these agents. The results of four ongoing trials combining immunotherapy with PARP inhibitors are eagerly awaited.
Where is innovation needed in the field to improve patient care?
Ovarian cancer is a rare disease, so it should become mandatory to refer women for centralised treatment in the multidisciplinary setting of a cancer reference centre: this alone has the potential to improve patients’ prognosis. To be able to save more lives in the future, our goal should additionally be to find a reliable way to diagnose women earlier: the five-year survival rate of patients with stage I ovarian cancer is 90%, but only half that much for stages III and IV. We now also have the possibility to prevent hereditary forms of the disease, so aiming to identify all patients with BRCA mutations would allow us to offer them risk-reducing strategies as well as the best tools of early diagnosis.