The results of our meta-analysis highlight that PARP inhibitors significantly improve progression-free survival in elderly patients with ovarian cancer. The administration of PARP inhibitors in patients aged ≥65 halves the risk of progression compared with placebo (HR=0.54; 95% CI 0.45 to 0.65, eight studies, 1435 patients), with an absolute effect of disease progressing in 223 fewer people for every 1000 receiving PARP inhibitors (95% CI from 283 to 157 fewer). The quality of the evidence was judged high. Therefore, we are confident that the true effect on progression-free survival lies close to that of the estimated effect on progression-free survival (Figure 4).

Summary of findings of the included studies for progression-free survival (PFS) in the old population.

The efficacy of PARP inhibitors in advanced ovarian cancer has been previously demonstrated both for the primary and the recurrent setting.18–20 22–24 26 However, the typical patients included in the clinical trials differ from those treated in daily clinical practice. The percentage of patients diagnosed with ovarian cancer at ≥65 years of age is high.1–5 The results of our meta-analysis confirm the efficacy and safety of PARP inhibitors for treating elderly patients, potentially filling the knowledge gap regarding the use of oncologic treatments in the elderly population.

Safety information is limited to hematologic toxicity. Older people seem to have a lower risk of severe anemia (p=0.04). This was an unexpected finding, especially considering the multiple risk factors for anemia in older patients, such as iron deficiency, the development of myelodysplastic syndromes, the reduced production of erythropoietin, and chronic kidney injury leading to reduced efficacy of erythropoietin.34 A hypothesis is that these effects could be influenced by age-related chronic inflammation due to the increased levels of circulating levels of pro-inflammatory cytokines, such as interleukin 2/6, interferon-γ, and tumor necrosis factor, that can be reversed by PARP inhibitors.35

Given the small sample size, further studies are needed to clarify the possible pathogenetic mechanisms. On the other hand, there is an increased risk of severe thrombocytopenia. No substantial differences have emerged between the elderly and the young population regarding non-severe hematologic adverse events and severe neutropenia. These are the first systematic data on this subset of patients. This is a population with multiple comorbidities, complicating treatments and limiting physicians’ choices. However, due to an increasingly aging population, developing effective and safe therapies for these patients is crucial. SOLO2 was the only study reporting data about the quality of life and dose modifications during olaparib therapy. There were no significant differences between elderly and young patients regarding dose modification/interruption and quality of life scores.27 This is in line with retrospective data deriving from an ancillary data analysis of eight prospective trials of patients aged ≥65 years with ovarian cancer treated with olaparib. Among the 398 patients, only 20% were aged ≥65 years. A total of 46.9% of patients younger than 65 required dose reduction compared with 44.7% of patients aged 65–69 years, 47.8% of patients aged 70–74 years, and 64.7% of those aged ≥75 years (p=0.62). Dose interruption occurred in 41.2% of patients younger than 65 years, and 50%, 43.5%, and 64.7% of patients aged 65–69, 70–74, and ≥75 years, respectively (p=0.11). Dose interruptions concerned 42.3% of those younger than 75 years and 64.7% of those aged ≥75 years (p=0.08). Despite the small sample size and not statistically significant differences, we should further investigate the dose attenuation when treating very old patients in prospective studies.36

In a sub-analysis of the PAOLA-1 study considering the cut-off age of 70 years, a slight increase of adverse events was reported among patients aged >70 than <70 patients treated with olaparib plus bevacizumab—for example, severe anemia occurred in 21.2% vs 16.5%, severe neutropenia in 9.7% vs 5.1% patients, severe hypertension in 26.9% vs 16.7%, respectively. Quality of life and geriatric assessment data are under evaluation.37 The age subgroup of patients older than 75 years was explored only by a post hoc exploratory analysis of the ARIEL3 trial. The small subset (n=25) of patients older than 75 years exhibited a non-significant benefit from rucaparib compared with placebo in progression-free survival (9.2 vs 5.5 months; p=0.16), with a similar safety profile in comparison with younger age subgroups. However, in this subgroup of patients, adverse events occurred in 69.9% of cases (vs 54% in the younger group), leading to dose reduction in 70.8% (vs 46.8%) of patients, and treatment discontinuation in 21.2% vs 11.9% of cases.38

To the best of our knowledge, this is the first systematic review and meta-analysis examining the efficacy and safety of PARP inhibitors in older patients with ovarian cancer. However, our analysis has several limitations: heterogeneity between the included trials, different PARP inhibitors and schedules in the included studies, lack of overall survival data, limited toxicity evidence, small number of trials with age stratification, and lack of individual patient data. Moreover, the platinum-resistant setting was not considered owing to a lack of age-stratified data at the time of the analysis. Very limited data exist regarding elderly patients; therefore, we could not include them in our meta-analysis. Finally, we have to emphasize that patients included in clinical trials are often selected for good general conditions and performance status 0–1: this could limit the applicability of our results to daily clinical practice, which is characterized by elderly patients with multiple comorbidities and concomitant medications with potential drug interactions. Thus, real-world studies should include a comprehensive geriatric assessment, evaluating functional and nutritional status, comorbidities and concomitant medications, depression and cognition, social activity, and support, to identify frailty risk or geriatric impairments that are not captured during the routine oncologic visit.39–42