Reassessing chemotherapy’s place in breast cancer treatment

An evidence-based answer arrives as to whether hormone therapy alone is inferior to hormone therapy plus chemotherapy
Tesaro begins building the case for checkpoint inhibitors as a standard treatment in solid tumours
Targeting the PIK3CA gene in breast cancer is effective, but patient benefit was more modest than anticipated

One of the talking points at ASCO was research showing that women with breast cancer may not need to take certain drugs after all. Richard Staines was in Chicago to find out more.

It’s fair to say that the side effects of chemotherapy are as feared as breast cancer itself – but new research presented at the conference showed that in some cases women didn’t need to include chemo in their treatment regimens.

For years standard care has combined chemotherapy with hormone therapy for a large group of women with breast cancer. But the results of the study show that for many women with hormone-receptor positive, HER2-negative axillary lymph node-negative breast cancer, treatment with chemo and hormone therapy is not more beneficial than with hormone therapy alone.

Findings from the TAILORx trial found that in around 70% of cases there is no need for chemotherapy. The study was supported by the National Cancer Institute, part of the US National Institutes of Health, and has been running since 2006.

Involving 10,273 women from 1,182 sites in the US, Australia and several other countries, it was designed to provide an evidence-based answer to whether hormone therapy alone is not inferior to hormone therapy plus chemotherapy. Based on results of the genetic test women were divided into a low-risk group that received only hormone therapy, and a high-risk group receiving both hormone therapy and chemotherapy. Those in a middle-risk group were randomly assigned to receive hormone therapy alone or hormone therapy with adjuvant chemotherapy.

It was the intermediate-risk group that was the focus of the study, which met its goal by showing the overall survival rate after five years in women receiving hormone therapy alone was 98%, compared with 98.1% for those who received both therapies. At nine years the respective OS rates were 93.9% and 93.8%.

Jeffrey Abrams, associate director of NCI’s Cancer Therapy Evaluation Program, said the findings would help support oncologists in their decision-making about the most appropriate treatments.

Tesaro’s checkpoint combination

Checkpoint inhibitors are becoming a standard treatment in many solid tumours, but as yet they have not made much impression in breast cancer.

US biotech Tesaro wants to change this and came to ASCO with new data supporting its decision to press ahead with a pivotal trial of a novel checkpoint inhibitor-based combination therapy.

Tesaro has developed its own PD-1 checkpoint inhibitor and wants to use it in combination with its already-approved poly (ADP-ribose) polymerase (PARP) class drug, Zejula (niraparib).

Trials of the PARP/PD-1 combination have so far taken place with Merck & Co.’s Keytruda (pembrolizumab), but Tesaro wants to avoid striking an expensive licence deal with one of the big pharma companies that already market checkpoint drugs.

Data released at ASCO 2018 is from TOPACIO, a phase I/II trial in ovarian cancer or triple negative breast cancer (TNBC). The results of the trial involving a combination of Zejula and Merck’s Keytruda suggest that the combination will produce the strongest response in patients with BRCA mutations. In this group, the median progression-free survival was 8.3 months, which compares favourably with standard chemotherapy, which usually stops the disease spreading for three to five months.

Tesaro has had talks with the FDA and is planning a registration study involving a combination of Zejula and its checkpoint inhibitor, codenamed TSR-042.

Roche axes PI3K drug

PI3K inhibitor class drugs have already been approved in blood cancer, but there is a scientific rationale to use them in solid tumours too.

Delegates at ASCO heard intriguing evidence from the SANDPIPER trial that targeting a common genetic abnormality in breast cancer, the PIK3CA gene, could be a potential new way to treat the disease. The study tested whether combining Roche’s PI3K inhibitor taselisib with fulvestrant was an improvement over fulvestrant and placebo.

The good news was that women on the combination treatment had a 30% lower chance of cancer worsening than those receiving only fulvestrant. Taselisib extended the time until cancer worsened by a median of two months (7.4 months with taselisib and fulvestrant versus 5.4 months on the control arm). The response rate, or tumour shrinkage, was more than doubled when taselisib was added (28% versus 11.9%), although overall survival data is not yet available.

But side effects are a known issue with this class of drugs, with heavy warnings on the box of Gilead’s PI3K blood cancer drug Zydelig (idelalisib) that have compromised its marketability. And with taselisib there were also safety issues, most common were diarrhoea (12%), hyperglycaemia (10%), colitis (3%) and stomatitis (2%). As a result, there was a high rate of discontinuations among women taking the combination – 17% versus 2% on the control arm – and more than a third of patients on taselisib reduced their dose.

Following the announcement of the results at ASCO, Roche went on record to say it will end its development of taselisib, citing the drug’s limited benefit and steep side effects as the reason. Another issue that emerged was that only study participants in North America and Europe seemed to benefit, with their cancer worsening being delayed by a median of 3.5 months – 7.4 months with the combination and 4.5 months on fulvestrant. But in other countries including Eastern Europe and Latin America, the drug seemed to produce little or no benefit, and ASCO’s experts called for more research into the cause of the discrepancy.

Presenting the findings, José Baselga, chief medical officer and medical oncologist at Memorial Sloan Kettering Cancer Center, said:

“Our findings are proof that targeting this pathway in breast cancer is effective. However, the benefit to patients was more modest than we hoped for, and there is a risk of considerable side effects with the addition of taselisib.

“But the challenges are considerable in terms of durability of effectiveness and toxicity.”

While patients and doctors will be disappointed about the outcome of the taselisib trial, experts at ASCO said there could be hope for drugs targeting this pathway.

But side-effects are the main stumbling block given that the drug only bought an incremental benefit over standard care. As seen from the reaction from TAILORx trial, making cancer therapies as tolerable as possible is important for patients, who may be unwilling to spend their final few months in discomfort and pain caused by drugs that are keeping them alive.

Richard Staines is Senior Reporter at pharmaphorum. He has been a journalist since the 1990s and has written for websites, newspapers and magazines. He has always had an interest in health, and has been focusing on the pharma industry since 2010, interviewing industry leaders and covering stories on topics including regulation, mergers and acquisitions, and the latest clinical developments.

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