The SOLO-1 trial was one of the “hot” topics at this year’s ESMO. A PFS improvement of 70% with good tolerance and efficacy not only in recurrences suggest a relevant innovation in the therapy of advanced ovarian cancer.
But from the beginning: Olaparib is a PARP inhibitor (poly-[ADP-Ribose] polymerases 1, 2 and 3). PARP enzymes are required to repair single-strand breaks in DNA. If this repair pathway is blocked in a specific way, namely via the action of olaparib, double-strand breaks occur in replicating cells, which also cannot be repaired in the simultaneous presence of pathogenic mutations such as BRCA1/2 and activate alternative, error-prone mechanisms. The lack of repair in the DNA ultimately leads to unsustainable instability of the genome over several rounds of replication, with death of the tumor cells (which are more exposed to DNA damage than normal cells). Lynparza® Film-Coated Tablets are approved in Switzerland as monotherapy for the maintenance treatment of patients with advanced, platinum-sensitive relapsed high-grade serous ovarian cancer following platinum-containing chemotherapy (in the presence of complete or partial remission).
SOLO-1
The question SOLO-1 was designed to answer in phase III was: Is olaparib also effective in the maintenance of newly diagnosed advanced carcinomas (i.e., not only in the relapse situation)? Is it reasonable and appropriate to use the new agent in certain patients already as a standard after successful first-line platinum chemotherapy and not only when the disease recurs?
You could cut it short and say: Yes, it is – at least in women with BRCA-mutated disease. 391 such patients with (mainly germline) mutation in either BRCA1, -2, or both, with newly diagnosed, advanced, “high-grade” serous or endometrioid disease and successfully completed platinum chemotherapy (partial or complete response) were randomized to the study. As in other studies, patients with fallopian tube cancer and peritoneal cancer were part of the sample because of similarity in tumorigenesis and shared tumor biology. After a median follow-up of more than three years, more than half of the olaparib maintenance group was still alive and progression-free (60.4%), while the proportion in the placebo group was less than half that at 26.9% (HR 0.3, 95% CI 0.23-0.41; p<0.001). The difference in median progression-free survival between placebo and olaparib was approximately three years according to sensitivity analysis. Table 1 shows some further results of the study. Of particular relevance is the so-called PFS2, which was also significantly improved by olaparib. Specifically, this means: The time to re-progression or death after subsequent therapy was also extended. Therefore, a detrimental effect of early olaparib on subsequent lines of therapy cannot be assumed.
The two comparator arms were well balanced at baseline, approximately 80% of patients had demonstrated a complete response to chemotherapy, and ECOG performance status was good. Most had undergone surgery, approximately 60% upfront surgery (over 70% of which had no residual macroscopic disease), approximately 30% cytoreductive interval surgery (over 80% of which had no residual macroscopic disease). The authors emphasized at the congress that this was a group that had relatively high chances for a “cure” already with frontline therapy alone. Thus, the hurdle for a significant result was probably relatively high.
The ovarian carcinoma
A 70 percent reduction in the risk of progression or death is an astonishingly good result when one recalls the characteristics of the disease: ovarian cancer is the fifth most common new cancer diagnosis among European women, with most of those affected being between 55 and 64 years old at the time. Around 16% of the most common types of ovarian cancer have a BRCA mutation.
Because detection in early stages is challenging, about three-quarters of women diagnosed already have advanced forms. Chemotherapy (after surgery) can interfere with tumor growth and slow or stop it – but it rarely prevents recurrence in the long term. Although standard therapy is given with curative intent, few patients with newly diagnosed advanced disease have any prospect of such a cure. After three years, more than 70% of all treated tumors recur. From this point on, the disease is usually considered incurable today. Therefore, the long-term survival rate (although increasing) remains low at just over 20% five years after diagnosis in stage III, and at 5% in stage IV.
Cure?
The sample from SOLO-1 is women with advanced disease. This picture is frequently encountered in everyday clinical practice. The aim is to protect such patients as well and as long as possible from the consequences of an (early) recurrence. At least for patients with BRCA-mutated tumors, the study seems to represent a major practical leap forward. A new standard is in the starting blocks. For the first time, the focus is on newly diagnosed carcinomas and not on recurrence, where, in addition to olaparib, other PARP inhibitors have made progress in recent years – partly dependent on, partly independent of the BRCA mutation – and have been approved in Europe (for recurrences occurring at least six months after platinum therapy was stopped).
Mortality, which is considered one of the highest compared to other cancers in women, could be massively reduced, i.e. death could be delayed, by earlier use of PARP inhibitor. Finally, in SOLO-1, nearly two-thirds of women were alive and progression-free after three years and still just over half were alive and progression-free after four years (versus 11% on placebo). In this context, it is relevant that study therapy was stopped after two years in the absence of disease evidence. In case of (stable) partial response it could be continued, in case of progression it was also stopped. Long-term follow-up observations will show how long the effect lasts. What is certain is that the Kaplan-Meier curves remained largely unchanged (i.e., did not converge further) even after two years and thus after therapy cessation.
Hopes are therefore high. Some experts are not afraid to use the word “cure” on a trial basis (which, however, can be defined differently in the case of cancer and is mainly declared on the basis of a certain survival time). Does the active ingredient actually increase the number of cured patients, and what is this proportion in the long term? In the future, will it not only be 20% of women in advanced stages who are still alive five years after diagnosis, but (significantly) more? At present, it is impossible to predict with certainty.
It is therefore necessary to wait – also until the data on overall survival are “mature”, i.e. until sufficiently high case numbers are available. This could – quite in the sense of the patients – still take some time (in view of the fact that the median PFS has not yet been reached either). Currently, the OS data maturity is 21%.
One conclusion can already be drawn: Early genetic testing, namely already at the time of diagnosis, is becoming increasingly important and could pose certain logistical problems in some regions.
Questions remain open about how the other PARP inhibitors will fare in the field, whether patients without BRCA mutations will benefit, and whether combination maintenance with olaparib and bevacizumab could provide further benefits. On the latter topic, the PAOLA-1 trial is ongoing, with results expected in 2019.
Compatibility good
The results are all the more relevant because the therapy was generally well tolerated. This is reflected not least in the unchanged health-related quality of life (HRQoL) since the start of the study with olaparib (Tab. 1) . Otherwise, the side effects corresponded to the known safety profile, were mostly of low severity, well controllable and, at about 12%, relatively rarely led to discontinuation of therapy. Of primary relevance were anemia and neutropenia, which were grade 3 or higher in 22% and 9%, respectively.
The study was published in the prestigious New England Journal of Medicine at the same time as it was presented at the congress [1].
Source: ESMO, October 19-23, 2018, Munich, Germany.
Literature:
- Moore K, et al: Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. NEJM 2018 October 21. DOI: 10.1056/NEJMoa1810858 [Epub ahead of print].
InFo ONCOLOGY & HEMATOLOGY 2018; 6(6); published Oct 25, 2018 (ahead of print).
