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From therapeutic nihilism to diversity in treatment options – what can be added?

Submitted by on 30 Mar 2016 – 17:11

Despite extensive use of radical treatments, such as surgery and radiotherapy, and constant technical innovations, mortality rates remain high. Prof Bertand Tombal, Consultant Urologist, Brussels Saint-Luc University Hospital lists out whats missing in the battle against prostate cancer

Prof Bertand TombalAccording to the International Agency for Research on Cancer (IARC), prostate cancer is the second most common cancer in men. An estimated 420,000 men were diagnosed with prostate cancer in Europe in 2012, accounting for 15% of the cancers diagnosed in men.

Despite extensive use of radical treatments, i.e. surgery and radiotherapy, and constant technical innovations, mortality rates remain high. IARC reported 101,000 deaths in Europe in 2012. Patients presenting upfront with disseminated metastases still uniformly die from the disease after a few years. Radical treatments fail to cure up to 30% of the patients diagnosed with a high-risk, undifferentiated, localized or locally advance disease. Ultimately most of them develop metastases and die from the disease.

Castration-resistant prostate cancer, an embarrassment of riches?

Since the seminal work of Charles Huggins, 1966 Nobel Prize’s laureate, suppressing testosterone, the male hormone, is the reference treatment for advanced metastatic prostate cancer. Hormone therapy induces dramatic responses but of short duration. In most cases, the tumour progresses in a stage of resistance. Complications, especially skeletal, occur rapidly and the issue is usually fatal within two to four years. In 2004, two drugs brought the first hope of cure. Docetaxel, a widely used chemotherapy, extends overall survival by three months and zoledronic acid, a bone targeting agent, delays the onset of bone complications by several months. Many patients, however, will never receive chemotherapy, being already in their late seventies or eighties when they develop CRPC.

Hopefully, four new drugs have entered the market since 2010. Enzalutamide and abiraterone are new hormones that increase overall survival and preserve quality of life in metastatic CRPC patients. Radium 223 is an injectable radionuclide that directly targets bone metastases, delays bone complications, and increase overall survival. Cabazitaxel is a taxane chemotherapy that is active in docetaxel-resistant patients. Finally, denosumab is a monoclonal antibody with slightly improved efficacy over zoledronic acid in preventing skeletal complications.

What seems an embarrassment of choices on paper is in fact a conundrum for the physicians. Each of these drugs reduces the risk of death by 20 to 30%. This looks appreciable at first sight, but, because the trials have been conducted at an advanced stage of progression, it translates into a survival benefit of merely 3 to 4 months. The late-stage disease niche was chosen because the purpose of the trials was to quickly register, and ultimately market, the new drugs. In addition, the benefit of these drugs is not synergic. For example, abiraterone and enzalutamide modes of action are similar resulting in “cross-resistance”. The patient progressing on a drug is very unlikely to benefit from the other. Finally, these drugs have not been tested against each other’s and physicians are left with no clue about the optimal timing for starting and stopping them and about the best sequence or combination of drugs.

What’s missing in the battle against prostate cancer?

Three factors, at least, are keys.

First of all, we need massive investment in large international academic platforms that independently study early use of drugs, sequence and combinations. Stampede and Chaarted are academic trials that have evaluated the benefit of docetaxel chemotherapy immediately at diagnosis in metastatic patients and not when the cancer was already resistant to castration. At that earlier stage, docetaxel confers an unprecedented increase in overall survival of 21 months; seven times longer than the benefit seen at the time of resistance to castration.

The benefit is impressive for the patient, practice changing, for a cost and a toxicity that is similar to a later use of the drug. Because these studies span over a decade, they challenge the conventional framework of industry’s patent protection. Docetaxel is generic now and the return for Sanofi, the original patent owner of docetaxel, is now negligible. This creates an obvious imbalance between industry sponsored studies proving that a drugs work and academic studies proving when a drug is the most efficient from an individual and a societal perspective. That is why new private-public-academic partnerships must be developed and conditional patent prolonging scenarios must be designed. This is crucial to support trial in cancer with long survival.

We need to fill the “translation gap” to understand who dies from cancer and what treatment is most likely to prevent this from happening. In the last decade, we have learned that prostate cancer is an extremely heterogeneous disease. Scientists understand much better the genetic and physiological determinants of this heterogeneity but very little of that knowledge is used by clinicians. Patients received broadly validated treatments merely taking into account their individual genetic characteristics. Achieving this will prove crucial in two situations. Firstly, to better identify the 30% of patients with high-risk localized cancer that die from the disease. It is a prerequisite to an early testing of the new drugs in that population. Secondly, to better select patients receiving expansive or toxic drugs to optimize the benefit and cost-efficiency and reduce inappropriate prescriptions. International precision medicine platforms are key initiatives to achieve that goal.

We need to normalize the quality of the delivery of care and include patients reported outcome in the treatment equations. Outside the strict framework of clinical trial, there is no pressure or incentive on clinicians to collect, analyse and report their results. Patients coping with the disease have no reference frame to decide where and how to be treated and what exactly they can expect from treatment. Healthcare providers, including governments, are mostly paying for prescriptions with no or little clue of performance. Considering the gigantic investment that will have to be made to treat cancer, is it still acceptable? The first and more important step is to secure robust acquisition of quality of indicators by every physician. Initiative conducted by ICHOM needs to be applauded since it provides the first set of consensually accepted indicators ready to be deployed.

Proven that we fulfil these three challenges the future of prostate cancer is bright

Prof Tombal is Chairman, Division of Urology, Cliniques universitaires Saint Luc, Brussels, Belgium and Chairman Clinical Trial Division, European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.