Exceptional Responses to PARP Inhibitors May Persist for Over Ten Years in Certain Patients with Recurrent Ovarian Cancer

A subset of patients with platinum-sensitive recurrent ovarian cancer achieves long-lasting responses to PARP inhibitors, but until now, little was known about their outcomes beyond the first five years without disease progression. An international study published in JAMA Oncology, featuring participation from the Sant Pau Research Institute (IR Sant Pau), shows that this benefit can be maintained over a extended period, as 78.7% of patients who had achieved an exceptional response (at least five years free of progression) remained progression-free at ten years from the start of treatment.

The study gathered data from 320 patients treated across 41 centers in 14 countries who had remained progression-free for at least five years from the start of maintenance therapy. Beyond describing their long-term outcomes, it provides insights into the safety of prolonged exposure and what happens when treatment is discontinued after several years. Among the study's authors is Dr. Cristina Martín-Lorente, a researcher in the Gynecological and Peritoneal Oncology Group at IR Sant Pau and an oncologist at Sant Pau Hospital, who contributed to the research.

An Exceptional Response That Raises New Questions

PARP inhibitors are targeted medications that prevent cancer cells from repairing specific types of DNA damage. They are used as maintenance therapy in select cases of ovarian cancer after the disease has responded to platinum-based chemotherapy. In the recurrent setting, current guidelines suggest continuing maintenance treatment until disease progression or until unmanageable side effects occur.

Early clinical trials with PARP inhibitors did not provide long-term follow-up data for patients remaining progression-free over extended periods, as this scenario was then exceptional. The emergence of this minority group with extraordinarily prolonged responses has raised new questions regarding the optimal duration of treatment, the risk of relapse after discontinuation, and the effects of continuous exposure over many years.

“Although we had observed for years that a small group of patients maintained extraordinarily long-lasting responses to PARP inhibitors, we had very little data on their long-term trajectory. This study offers insights that help us better understand the natural history of these exceptional responses and can facilitate shared decision-making with patients, although many questions remain to be answered,” explains Dr. Cristina Martín-Lorente.

The study defined an exceptional response as remaining progression-free for at least five years from the initiation of the PARP inhibitor. Participants had a median age of 56, had received a median of two prior lines of chemotherapy, and received maintenance therapy for a median of 75 months—slightly more than six years. After a median follow-up of 6.8 years, 88.8% remained progression-free at seven and a half years, and 78.7% remained progression-free at ten years. The estimated overall survival rate at ten years was 90.5%.

Although overall outcomes were highly favorable, the risk of relapse did not disappear completely. A total of 34 patients experienced disease progression after passing the initial five-year mark, with the latest event occurring 14.8 years after initiating treatment. The only baseline clinical characteristic independently associated with a more favorable outcome was an interval of at least 18 months between initial diagnosis and first relapse.

What Happened After Treatment Discontinuation

At the time of analysis, 211 patients were actively receiving the PARP inhibitor, and 109 had discontinued treatment. In 85 cases, treatment was stopped for reasons apart from disease progression, such as clinical judgment, adverse events, patient preference, or other medical circumstances. These patients demonstrated an estimated ten-year progression-free survival rate of 90.1%, compared to 72.5% among those who remained on therapy. However, the authors caution that this comparison must be interpreted carefully. The study is retrospective; patients were not randomized, and those who stopped treatment may have possessed particularly favorable baseline clinical profiles.

“The findings do not suggest that PARP inhibitors should be routinely discontinued, nor do they prove that stopping treatment is equivalent to continuing it. What they show is that in a carefully selected subgroup of patients without signs of progression, stopping therapy after several years did not appear to be associated with an obvious worsening of outcomes,” notes Dr. Martín-Lorente.

Six patients who discontinued treatment before progression subsequently relapsed. The time between discontinuation and relapse ranged from one to 64 months, underscoring the need for individualized decision-making and continued clinical monitoring.

These findings should be viewed as hypothesis-generating and do not support the conclusion that discontinuing treatment is equivalent to maintaining it in patients with sustained responses.

The Role of BRCA1 and BRCA2 and Long-Term Safety

Approximately 73% of patients harbored a known pathogenic variant in BRCA1 or BRCA2, key genes involved in DNA repair. The study also identified an enriched presence of variants localized within specific functional domains, particularly the RING domain of the BRCA1 protein and the DNA-binding domain of the BRCA2 protein.

These findings suggest that beyond the mere presence of a genetic alteration, its specific domain location and functional impact may influence the likelihood of achieving an exceptional response. However, these results stem from an exploratory analysis and require independent validation.

Regarding safety, 43.1% of participants required at least one dose reduction, primarily due to hematologic toxicity or fatigue, while 6.9% discontinued treatment due to adverse events. Five patients—1.6% of the cohort—developed a myelodysplastic syndrome or acute myeloid leukemia. These hematologic malignancies represent a known risk associated with PARP inhibitors and prior exposure to platinum-based chemotherapy; however, their incidence remained low in this long-term treated population.

Moving Toward More Individualized Decisions

The study's findings raise the hypothesis that in a highly selected group of patients with sustained exceptional responses, prospective research could evaluate whether treatment discontinuation after several years of maintenance is a safe strategy. However, given its retrospective and non-randomized design, these findings cannot be used to establish definitive recommendations regarding optimal treatment duration or alter current clinical practice.

The authors suggest that some patients may have achieved what they term a functional cure, defined as the ability to remain disease-free for many years even after treatment withdrawal. Nevertheless, the occurrence of late relapses warrants caution and necessitates extended follow-up.

“This study demonstrates the existence of a patient subgroup with an extraordinarily favorable outcome that was previously poorly characterized. It highlights that exceptional responders form a biologically distinct cohort whose further characterization could help personalize treatment duration in the future and shed light on the mechanisms underlying sustained PARP inhibitor sensitivity. The next step will be to identify predictive biomarkers to prospectively identify these patients and validate these strategies in specifically designed clinical trials,” concludes Dr. Martín-Lorente.

In the future, emerging tools such as circulating tumor DNA analysis may assist in detecting minimal residual disease and better selecting suitable candidates for treatment withdrawal. For now, this study does not establish a universal optimal treatment duration or alter current guidelines, but it offers valuable evidence to guide clinical decision-making in this exceptional patient population.

Reference Article:

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