AstraZeneca’s Phase III pipeline is growing ahead of plan, chief executive  Pascal Soriot told a recent media briefing, and cancer drugs make up a major chunk of the pipeline.

In oncology, olaparib for solid tumours, moxetumomab pasudotox for hairy cell leukaemia and selumetinib for non-small cell lung cancer are expected to be key players. Also showing potential are AZD9291 a ‘third generation’ tyrosine kinase inhibitor for NSCLC, and from AstraZeneca’s biologics R&D arm MedImmune, MEDI4736, a PD-L1 monoclonal antibody that is being studied in patients with advanced solid tumours.

Within AZ’s oncology franchise, the breast cancer portfolio has been targeted for expansion and a raft of new combination therapies is under investigation,. However substantial growth is expected from established agents such as Faslodex (fulvestrant).

AZ undoubtedly took their eye off the ball with Faslodex, taking too long to market entry and then launching a dose (250mg) that proved suboptimal. Since then, the CONFIRM data has revealed that a higher (500mg) dose improves both progression-free and overall survival in postmenopausal women with oestrogen receptor–positive advanced breast cancer.

The higher dose has now rolled out into clinical practice and was recently incorporated into new European and US guidelines for the treatment of advanced breast cancer. According to Gary Nunn, global products manager for oncology brands for AstraZeneca, the elements are now in place for Faslodex to really take off.

“It has taken us a while to really ramp up fulvestrant. Initially it was difficult to formulate and it took us a while to sort out the dose that would provide the patient benefits we knew the pharmacology could deliver,” he told PharmaTimes. “The kick-up really came when we launched the 500mg dose – then we really started to see an improvement in efficacy over other endocrine agents.  

Since then, he added, "it has become established in the physician’s armamentarium for treating endocrine responsive metastatic disease.” Nunn went on to say that "yes there will be combinations coming along, but for women whose tumours express the oestrogen receptor, we will still need to modulate that drive on the tumour, irrespective of what else we add.”

Nunn sees fulvestrant as the 'backbone’ for a broad range of combination therapies for advanced breast cancer. “As resistance develops, we can attack the tumour via these other signalling pathways, combining different drug modalities with Faslodex.  We have several  pipeline agents which potentially can be added to Faslodex to improve efficacy for women with breast cancer".

The Novartis mTOR inhibitor everolimus is a prime example. Currently this has been combined with the aromatase inhibitor letrozole, but Nunn sees scope for a Faslodex combination:  “There is already some Phase II data in the public domain, so that is an area for investigation. There is also potential for combining Faslodex with our investigational mTOR inhibitor AZD2014”.

Greater collaboration between big pharma

Nunn predicts greater collaboration between major pharma companies servicing this field. “An area of great interest is the CDK46 group of drugs and the most advanced of these is palbociclib from Pfizer. We are collaborating with Pfizer in a study of Faslodex in combination with their drug. The PALOMA 3 trial has already started."

Nunn  also noted that "colleagues at Novartis are combining their PI3 kinase inhibitor BKM120 with Faslodex in patients With HR+,HER2-, AI-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor therapy” (the BELLE-3 study).

The poly ADP-ribose polymerase (PARP) inhibitor olaparib, which has been filed for  European Union approval for ovarian cancer has potential for activity in a range of tumour types with DNA repair deficiencies. Trials in patients with germline BRCA1/2 mutations and high-risk HER2 negative primary breast cancer are also slated to start soon.

There is a range of time horizons for these developments. Phase III palbociclib/Faslodex and for BKM120/Faslodex is expected within the next two to three years, while data on Medi4736 and olaparib are expected to be presented in Chicago at this year’s ASCO meeting. Recruitment into the FALCON study (Faslodex versus AstraZeneca's own Arimidex (anastrozole) closes this year, with preliminary data expected at December’s  San Antonio Breast Cancer Symposium.