EXPERT ANALYSIS FROM ICACT 2015

PARIS (FRONTLINE MEDICAL NEWS)Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial ( Lancet 2010;376:1155–1163 ) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS ( J. Clin. Oncol. 2012;30:2039-45 ) and AURELIA ( N. Engl. J. Med. 2011;365:2484-96 ) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study ( N. Engl. J. Med. 2012:366:1382-92 ) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

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