Independent research with drugs without commercial interest is today very difficult to realise and at the same time particularly challenging. The increasingly high cost of clinical trials, the difficult competition with industry-funded and highly remunerative clinical trials with commercial purposes, are major obstacles for the realisation of clinical trials with drugs without commercial interest, such as repurposing low-cost drugs. The Anticancer Fund aims to address this issue, by supporting trials of promising drugs, regardless of their commercial value.

Insights from the PIONEER-trial

This year at the international San Antonio Breast Cancer Symposium (SABCS), the largest scientific conference dedicated to breast cancer, Rebecca A. Burrell from the Cancer Research UK Cambridge Centre, presented the results of the PIONEER trial, a clinical trial to treat women with ER-positive breast cancer.  

PIONEER is a window-of-opportunity trial evaluating the addition of the progesterone receptor (PR) agonist megestrol to letrozole for early-stage oestrogen receptor (ER) positive breast cancer, aiming to exploit the ER-PR interaction. The study, which was led by Dr Richard Baird, recruited postmenopausal, untreated ER+ HER2- primary breast cancer patients, stratified by grade, histology, and ER score. The study design included three treatment arms: A) Letrozole alone; B) Letrozole + Megestrol 40 mg daily; C) Letrozole + Megestrol 160 mg daily. Patients received the study drugs during a window of 15 days (13-19) between diagnosis and surgery. Tumour samples were collected before treatment and compared with those from the surgery.

The primary endpoint was tumour proliferation change in KI67 in Arm A vs B+C, and the secondary endpoints included change in Aurora Kinase A, end of treatment KI67, and safety and tolerability.

Translating lab discoveries into a clinical trial

This study seems to have confirmed what had already emerged from the experimental data coming from Prof Jason Carroll’s lab in Cambridge as well. In particular, the authors reported a greater reduction in proliferation (KI67) at end of treatment with megestrol and letrozole vs letrozole alone (p = 0.013). Furthermore, lower doses of megestrol are sufficient to achieve this anti-proliferative effect. The treatment was very well tolerated. The authors concluded that adding lower dose megestrol (40mg daily) to aromatase inhibitor treatment could be a low-cost way to enhance the anti-tumour effect and might additionally increase compliance through alleviating hot flash symptoms.

In the context of drug repurposing studies, this study is to be welcomed with great interest and the authors are to be congratulated for managing to translate preclinical data into a clinical trial using a low-cost drug - considered by many as obsolete - recruiting over 240 patients at 10 UK sites. Major credit is therefore due to the authors for their determination and efforts in making this happen, and great credit is also due to the Anticancer Fund that funded the study.

This is an important example of how it is possible to carry out a study on drug repurposing amidst multiple difficulties, especially economic ones.

Encouraging results paving the way for future clinical developments

The results are very encouraging because they confirm on a clinical level what the preclinical studies highlighted several years ago.

These decidedly intriguing results open new perspectives and potential opportunities that clearly need to be further developed and verified. In particular, what has been observed with this study on the reduction of Ki-67 can be further developed to verify and evidence what the real clinical benefit may be in terms of clinical improvement, such as an increase in responses and time to progression in the metastatic phase, or in the percentage of pathologic responses in the neoadjuvant phase, or even better in terms of disease-free survival in the adjuvant phase.

Defining clinical value: challenges and merits

The definition of the setting of patients in which to develop new studies will certainly be essential to be able to define the real clinical value better and quickly of what has just been presented at SABCS with this hormonal combination.

When talking about clinical value, in addition to therapeutic efficacy it will also be necessary to understand what the improvement in terms of quality of life as well as side effects might be. Should the improvement in clinical efficacy be confirmed, the repurposing of a low-cost drug would definitely be a further relevant point of merit for this line of research.