The current standard frontline therapy for advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer includes a combination of surgical cytoreduction and at least six cycles of platinum-based chemotherapy. While this achieves a complete clinical response (“remission”) in most, 85% of patients will recur and eventually succumb to the disease. This suggests that treatments are good at inducing remission, but poor at eradicating the disease altogether. This has motivated the consideration of maintenance therapy: extended treatment beyond completion of chemotherapy during the period of time when patients are clinically disease free.
Maintenance therapy is an appealing concept for clinicians who desperately want to “hold” their patients in a disease-free state for longer periods. It is also a profitable way to administer therapy as there is more compensation to the pharmaceutical industry from chronic, long-term drug administration rather than episodic treatment courses. However, the following question must be asked: Is this extended therapy worthwhile for all patients, and is it good value?
In the past 12 months, three major industry-sponsored clinical trials have been published (PRIMA, PAOLA-1, and VELIA)which suggest a benefit for all patients with advanced epithelial ovarian cancer in receiving prolonged poly (ADP-ribose) polymerase inhibitor (PARPi) therapy after primary chemotherapy.1-3 This has resulted in Food and Drug Administration approval for some of these agents as maintenance therapy. Despite differences in the drugs tested and the timing of therapy, these studies observed that treatment of advanced ovarian cancer with the addition of a PARPi during and/or after carboplatin and paclitaxel chemotherapy for up to an additional 3 years resulted in a longer progression-free survival (PFS) of approximately 6 months. PFS is defined as the time to measurable recurrence or death. However, this positive effect was not equally distributed across the whole population; rather, it appeared to be created by a substantial response in a smaller subgroup.
PARP inhibitor therapies such as olaparib, niraparib, veliparib, and rucaparib target a family of enzymes that repair DNA and stabilize the human genome through the repair of single-stranded DNA breaks. Inhibiting these enzymes facilitates the accumulation of single-stranded breaks, allowing the development of double-strand breaks, which in turn cannot be repaired if the cell has deficient homologous recombination (HRD) such as through a germline or somatic BRCA mutation, or alternative relevant mutation that confers a similar effect. The opportunistic pairing of a drug interaction with a pathway specific to the cancer is an example of a targeted therapy.
In order to improve the value of cancer drug therapy, there has been emphasis by cooperative research groups, such as the Gynecologic Oncology Group, to study the efficacy of targeted therapies, such as PARPi, in patients identified by biomarkers such as tumors that possess germline or somatic HRD in whom they are most likely to work. This approach makes good common sense and promises to deliver a large magnitude of clinical benefit in a smaller focused population. Therefore, even if drug costs are high, the treatment may still have value. Consistent with that principle, the recently published VELIA, PRIMA, and PAOLA-1 trials all showed impressive benefit in PFS (on average 11-12 months) for the subgroup of patients with HRD. However, these studies were designed and funded by the pharmaceutical industry, and abandoned the principle of biomarker-driven targeted therapy. They did not limit their studies to the HRD-positive population most likely to benefit, but instead included and reported on the impact on all-comers (patients with both HRD and HR-proficient tumors). Subsequently their final conclusions could be extrapolated to the general population of ovarian cancer patients, and in doing so, a larger share of the marketplace.
Only 30% of the general population of ovarian, fallopian tube and primary peritoneal cancer patients carry a germline or somatic BRCA mutation and less than half carry this or alternative mutations which confer HRD. The remaining majority are HR-proficient tumors. However, the three study populations in the aforementioned trials were enriched for HRD tumors with 50%-60% subjects carrying germline or somatic HRD. Therefore, it is likely that the observed benefits in the “intent-to-treat” group were larger than what a clinician would observe in their patient population. Additionally, the large (11-12 month) gains in the HRD-positive group may have been so significant that they compensated for the subtle impact in the HR-proficient population (less than 3 months), resulting in an average total effect that, while being statistically significant for “all comers,” was actually only clinically significant for the HRD group. The positive impact for HRD tumors effectively boosted the results for the group as a whole.
The use of PFS as a primary endpoint raises another significant concern with the design of these PARPi maintenance trials. Much has been written about the importance of PFS as an endpoint for ovarian cancer because of confounding effects of subsequent therapy and to minimize the costs and duration of clinical trials.4 PFS is a quicker, less expensive endpoint to capture than overall survival. It usually correlates with overall survival, but typically only when there is a large magnitude of benefit in PFS. These arguments are fair when considering episodic drug therapies in the setting of measurable, active disease. However, maintenance therapy is given during a period of what patients think of as remission. Remission is valued by patients because it is a gateway to cure, and also because it is a time devoid of symptoms of disease, toxicity (therapeutic and financial), and the burden of frequent medical visits and interventions. While PFS is a measure of the length of remission, it is not a measure of cure. We should ask: What does it mean to a patient if she has a longer remission but needs to be on drug therapy (with its associated burdens and toxicities) in order to maintain that remission? We know that an increase in PFS with maintenance therapy does not always result in a commensurate increase in survival. One does not always precede the other. An example of this is the use of maintenance bevacizumab following upfront chemotherapy which improves PFS by 4 months, but is not associated with an increase in survival.5
When considering the value and ethics of maintenance therapy, it should be associated with a proven survival benefit or an improvement in quality of life. With respect to PARPi maintenance, we lack the data regarding the former, and have contrary evidence regarding the latter. In these three trials, PARPi maintenance was associated with significantly more toxicity than placebo including the commonly observed nausea and fatigue. Most of us would not like to be on a drug therapy for 3 years that made us feel nauseated or fatigued if it didn’t also increase our chance of cure or a longer life. While the significant PFS benefit of maintenance PARPi that is consistently observed in HRD-positive ovarian cancers suggests there will also likely be a clinically significant improvement in survival and cure in that specific subpopulation, this is less likely true for the majority of women with HR-proficient ovarian cancers. Time will tell this story, but as yet, we don’t know.
The use of maintenance PARPi therapy during and/or after primary cytotoxic chemotherapy for advanced epithelial ovarian, primary peritoneal, and fallopian tube cancer is associated with a substantial benefit in time to recurrence in a population with HRD tumors and a small benefit among the majority who don’t. However, it comes at the cost of toxicity at a time when patients would otherwise be free of disease and treatment. I propose that, until a survival benefit for all women has been observed, we should consider a targeted and biomarker-driven approach to maintenance PARPi prescription, favoring prescription for those with germline or somatic HRD mutations.
Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at [email protected].
1. González-Martín A et al.
2. Ray-Coquard I et al.
3. Coleman RL et al.
4. Herzog TJ et al.
5. Tewari KS et al.