There is genuine excitement within the gynecologic cancer clinical and research communities for the potential role of PARP inhibitors in the management of ovarian cancer.
Maurie Markman, MD
Preclinical data have provided a strong rationale for the potential clinical utility of poly(ADP-ribose) polymerase (PARP) inhibitors in the management of patients with epithelial ovarian cancer who have known mutations (germline or somatic) in BRCA. Clinical experience, both in the phase II and phase III trial settings, has confirmed substantial biological and clinical activity for this class of antineoplastics in disease management. Further, there is evidence for the utility of PARP inhibitors in ovarian cancers in the absence of BRCA mutations (germline or somatic), presumably resulting from other molecular deficiencies in DNA repair.
There are currently 3 PARP inhibitors approved by the FDA for commercial use, each with different clinical indications. Although these agents appear to have somewhat different toxicity profiles, to date there have been no direct comparisons among the drugs. Ongoing trials in ovarian cancer are exploring additional clinical indications and novel strategies designed to combine PARP inhibitors with other antineoplastics (eg, antiangiogenic agents, checkpoint inhibitors).
There is genuine excitement within the gynecologic cancer clinical and research communities for the potential role of poly(ADP-ribose) polymerase (PARP) inhibitors in the management of ovarian cancer. Since the introduction of paclitaxel into the oncologist’s armamentarium more than 20 years ago, there have been a paucity of phase III trial data challenging the existing treatment paradigms, and even where such data exist, they often generate as much controversy as they actually change current thinking regarding current disease management (eg, neoadjuvant chemotherapy, intraperitoneal platinum drug delivery, paclitaxel maintenance treatment). An important exception to this statement are data related to the delivery of bevacizumab in the management of ovarian cancer in several settings, but even here the optimal use of this strategy remains to be defined.
In addition to impressive and provocative trial data (highlighted below), including striking differences between treatment and control arms in several randomized, double-blind, placebo-controlled clinical trials, the observation that there are currently 3 PARP inhibitors approved for routine clinical use in the United States in the management of ovarian cancer is testimony to both the utility of this class of drugs and the realistic potential that these agents will favorably affect the natural history of the malignancy in a substantial proportion of individuals.
Clinical Trials of PARP Inhibitors in Ovarian Cancer
Preclinical data demonstrating that both the BRCA and PARP pathways are critically relevant to the fundamental process of DNA repair, and subsequent studies demonstrating that inhibition of PARP (through the introduction of a drug that interferes with PARP function) produces profound cell kill in cells genetically deficient in BRCA, have resulted in the clinical exploration of the utility of such inhibition in patients with ovarian cancer who have known germline BRCA mutations.1
Olaparib, the first PARP inhibitor to be introduced into the clinic for the treatment of ovarian cancer, has been shown in several studies to possess an impressive degree of single-agent activity (approximately 30% to 50% response rate) when employed as a second-line (or later) strategy in the presence of BRCA mutations.2-7Clinical activity was most commonly noted in the platinum-sensitive patient population, although individuals with platinum-resistant cancers were also documented to respond. Further, clinical activity has also been observed in high-grade serous ovarian cancers in the absence of a BRCA mutation, although the response rates are lower in this setting.
In a subsequently conducted landmark double-blind, randomized phase II trial, patients with high-grade ovarian cancer in a second remission following platinum-based chemotherapy received either olaparib or placebo following discontinuation of the cytotoxic regimen, after attaining an objective response or achieving a state of stable disease.8The study revealed a highly statistically significant improvement in progression-free survival (PFS) (median 8.4 months vs 4.8 months; HR, 0.35; P <.001) in favor of the active treatment. Perhaps of greatest interest, the patient population with a documented germline BRCA mutation experienced almost a tripling of the time to subsequent disease progression (median 11.2 months vs 4.3 months; HR, 0.18; P <.001).9A final report of the long-term follow-up of this study revealed the provocative suggestion for a favorable impact of the maintenance strategy on overall survival.10
The preliminary results of a subsequently conducted randomized phase III trial of olaparib compared with placebo in patients with platinum-sensitive recurrent ovarian cancer who were in a complete or partial response after 2 or more lines of platinum-based therapy have recently been reported with a very similar outcome observed.11The overall median PFS for active maintenance therapy versus placebo was 19.1 months versus 5.5 months, respectively (HR, 0.30; P <.001).
Although olaparib is currently approved by the FDA for the single-agent treatment of patients with ovarian cancer with a documented germline BRCA mutation who have received a minimum of 3 prior lines of cytotoxic chemotherapy, it is likely that the recently reported phase III trial data will extend the drug’s clinical indications.
Rucaparib, a second PARP inhibitor, has been approved by the FDA for single-agent treatment of women with ovarian cancer who have either a germline or somatic mutation of BRCA and who have received a minimum of 2 prior lines of chemotherapy. The phase II trial data supporting this indication revealed an objective response rate (ORR) of approximately 80% in patients with a BRCA mutation.12
In a group of patients treated in the absence of a BRCA mutation and who were characterized as having a high level of loss of heterozygosity, an ORR of 44% was observed. In contrast, in the presence of a low level of loss of heterozygosity, only 20% of treated patients experienced a response.12These data support the hypothesis that defects in DNA repair mechanisms in individual cancers other than BRCA may be appropriate targets for therapy with a PARP inhibitor.
The favorable results of a randomized phase III trial examining the use of rucaparib in the second-line maintenance setting has recently been reported in a press release from the manufacturer of the agent. However, further discussion of the relevance of these data awaits their presentation at an appropriate scientific venue and subsequent publication in the peer-reviewed medical literature.
Niraparib, the third PARP inhibitor available for use in the United States, has specifically been approved for maintenance therapy following the attainment of a second-line (or later) response (complete or partial) to platinum-based chemotherapy. The approval was based on the results of a randomized phase III trial that examined the utility of this agent compared with placebo in this clinical setting.13In women with BRCA-mutation-positive ovarian cancer, the median PFS (following randomization) was 21 months compared with 5.5 months for placebo (HR, 0.27). In the overall nongermline BRCA patient population entered into this study, the median PFS was 9.3 months compared with 3.9 months (HR, 0.45), in favor of niraparib treatment.13
Of note in the niraparib trial, similar to the reported experience with rucaparib, a biomarker was evaluated for the purpose of identifying patients whose cancers might be particularly susceptible to this PARP inhibitor despite the absence of a germlineBRCAmutation. In fact, in patients without a germlineBRCAmutation whose cancers were found to be homologous recombinant deficiency (HRD) positive, maintenance therapy with niraparib resulted in a median 12.9-month PFS compared with 3.8 months (HR, 0.38) with placebo.13However, since even in the absence of the cancer being HRD positive there was a statistically significant improvement in PFS associated with niraparib treatment, the FDA elected to approve the agent for routine administration as a second-line maintenance strategy (following a response to platinum-based treatment) without requiring the use of a molecular biomarker (either BRCA mutation or HRD-positive).
Choice of PARP Inhibitors in Ovarian Cancer
To date, in the absence of any direct trial-based comparison among the 3 commercially available PARP inhibitors or other agents in clinical development, it is not possible to make any definitive statement regarding the relative efficacy or toxicity of the individual drugs. To date, the agents have received regulatory approval for use in different clinical settings, although based on reported trial results, this situation may change in the near future.
Currently available data suggest somewhat different adverse event (AE) profiles for the individual agents. However, the large majority of patients in the nonrandomized and randomized trial experiences for all 3 drugs were found to be able to continue with therapy (as permitted by the protocol) despite documented toxicity following appropriate dose modifications and treatment interruptions (to permit recovery from the AEs).2-13
Considering the fact that currently available PARP inhibitors are oral agents, it is critical to acknowledge the relevance of even low-grade nausea that may seriously interfere with the willingness of an individual patient experiencing such toxicity to continue with the agent. This concern may be particularly relevant in the maintenance setting, in which a patient who is feeling relatively well and is without cancer-related symptoms may have great difficulty considering taking a medication that can result in a meaningful deterioration in quality of life. Therefore, considerable effort needs to be undertaken by the clinical team to attempt to avoid treatment-related emesis as much as possible. In fact, the continued presence of this AE in a patient, despite efforts to control the symptoms, may be a highly appropriate indication to consider the use of an alternative PARP for that individual.
Future Development of PARP Inhibitors in Ovarian Cancer
Ongoing trials are exploring a number of highly clinically relevant questions related to the use of PARP inhibitors in ovarian cancer, including their use as first-line maintenance strategy.
One obvious issue requiring examination is the potential for clinically meaningful noncross-resistance among the currently commercially available (or still investigative) PARP inhibitors. The so-called PARP-after-PARP strategy might be considered in a patient who has failed to respond to 1 PARP agent or who has initially responded but has now progressed.
Alternatively, the question is relevant for maintenance therapy after different lines of platinum-based treatment or nonplatinum cytotoxic agents. For example, 1 PARP agent might be utilized as first-line maintenance, with a different PARP drug employed following a second-line response to a platinum agent and another PARP inhibitor as third-line maintenance.
Other highly clinically relevant questions in ovarian cancer management include the possible addition of a PARP agent to standard platinum-based cytotoxic therapy, or in combination with bevacizumab (currently a standard-of-care agent in the malignancy), or potentially with a checkpoint inhibitor (currently solely an investigative strategy).
In discussions regarding the use of PARP inhibitors in ovarian cancer, it remains relevant to acknowledge the legitimate concern for the potential development of a myelodysplastic syndrome (MDS) or acute leukemia. Fortunately, to date, the data regarding this devastating toxic effectresulting from prior DNA damage because of potent cytotoxic chemotherapy, and the theoretical concern for the clinical consequences of interference with the body’s DNA repair mechanisms—have been very reassuring. The overall risk of MDS and acute leukemia following treatment with a PARP inhibitor appears to be less than 2%, with many patients having received more than 5 years of continuous PARP inhibitor therapy. However, with the durations of treatments anticipated to become even longer, the far greater numbers of patients soon to be receiving such therapy, and the ongoing exploration of additional novel combination strategies employing PARP agents, careful observation and full reporting of this serious event are required.