PARP Inhibitors for Recurrent Ovarian Cancer: No 'Embarrassment of Riches' Just Yet
Results of studies in ovarian cancer with agents bevacizumab and pazopanib has “raised the bar” for median progression-free survival.
CHICAGO—Results of studies in platinum-resistant recurrent ovarian cancer with the antiangiogenic agents bevacizumab and pazopanib has “raised the bar” for median progression-free survival to greater than 6 months, and this is the new “bar” that PARP inhibitors have to exceed, attendees at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting were told during a poster discussion session.
Similarly, in platinum-sensitive disease, three studies with bevacizumab and cediranib, OCEANS, GOG213, and ICON6, have increased median progression-free survival to 12.4, 13.8, and 11.1 months, respectively, said Jonathan A. Ledermann, MD, of University College London Cancer Institute in London, United Kingdom.
It is in this context that he discussed two presentations, “a phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation,” by Shapira-Frommer and colleagues,1 and “phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C ) in heavily pretreated high-grade serous ovarian cancer (HGSOC) at low genetic risk,” by Chiou and colleagues.2
In his talk, “Embarrassment of Riches: PARP Inhibitors versus Antiangiogenics,” Dr. Ledermann reviewed what is known about PARP inhibitors and antiangiogenic therapy in recurrent ovarian cancer, what can be learned from the two presentations he was discussing, and where oncologists can go next in making choices for therapy and designing new trials to improve outcomes.
In the 1990s, patients with recurrent ovarian cancer could be rechallenged with platinum agents, based on whether they were “platinum sensitive” or “platinum resistant.” In the 2000s, the option was combination or single agent chemotherapy and now, in the 2010s, with the molecular targeted therapies—affecting angiogenesis and inhibition of DNA nuclear repair—the options include whether to administer as a single agent, in combination, on what schedule, and in what order, he explained.
The phase 2 study evaluated the efficacy and safety of rucaparib, a potent oral PARP, in patients with platinum-sensitive, relapsed germline BRCA mutations and high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Of the 40 patients, 68% had a median PFS of 6 to 12 months and 27%, a median PFS of greater than 12 months, with 15 of 23 responses ongoing up to 40 weeks or more; 66% (23 of 35 patients) had achieved RECIST response. The most common adverse events (AEs) were fatigue, gastrointestinal toxicities, and transaminase elevations that were transient and self-limiting, with no other evidence of liver dysfunction.
Dr. Ledermann said these results raise the questions, “Should rucaparib be used as single agent therapy in platinum-sensitive disease, or as maintenance?” and “How will it perform in platinum-resistant disease?”
The phase I/Ib study added olaparib to escalating doses of carboplatin; of the 30 patients, 11 had platinum-sensitive ovarian cancer and 19 patients had platinum-resistant ovarian cancer.
The median number of prior therapies was six. The overall response rate was 36% in platinum-sensitive disease and 7% in platinum-resistant disease.
The most common AEs were neutropenia, thrombocytopenia, and anemia. Dr. Ledermann said a randomized trial with carboplatin/olaparib would be needed to test this combination in the platinum-resistant population.
In summarizing the data in pretreated patients with platinum-sensitive BRCA mutated ovarian cancer, he said high response rates to both rucaparib and olaparib were shown, with good disease control. The questions these studies raise are, “Should PARP inhibitors be used earlier, as maintenance, or reserved for later stage disease?” “Should they be used in platinum-sensitive or platinum-resistant ovarian cancer?” and “Will patients respond to retreatment with a different PARP inhibitor?”
Dr. Ledermann said there is emerging evidence of the benefit of combining antiangiogenic agents with olaparib, such as cediranib and olaparib compared to olaparib alone in platinum-sensitive patients; to date, activity appears to be greater in wild type compared with mutated BRCA.
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New trials in design include PAOLA1, first-line therapy with bevacizumab plus olaparib maintenance, and three trials in platinum-sensitive relapse: NCI-CTEP, cediranib plus olaparib compared with chemotherapy; ENGOG Ov24 (ANANOVA), niraparib and bevacizumab with chemotherapy; and ICON 9, chemotherapy and cediranib with olaparib plus cediranib compared with cediranib maintenance.
“So, finally, the question is, ‘do we have an embarrass de richesses,' an embarrassment of riches? The answer is ‘no,'” Dr. Ledermann said. “We have two new classes of agents, both active, and patients need both these, but making choices really is quite hard, and quite a lot of research is going to be needed to look at the timing of these treatments. Pharma have given us these drugs; the development has been excellent, but we as clinicians now need to focus on the needs of our patients and integrating these, looking at the right combinations, looking at the right targets, and selecting the right patients, and that's a challenge for us all.”
- Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol. 2015;33:(suppl; abstr 5513).
- Chiou VL, Kohn EC, Annunziata CM, et al. Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in heavily pretreated high-grade serous ovarian cancer (HGSOC) at low genetic risk (NCT01445418). J Clin Oncol. 2015;33:(suppl; abstr 5514).