Emerging management of metastatic castration-sensitive prostate cancer: front-line chemotherapy vs. oral therapy

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Published: 8 May 2019
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Prof Jorge A. Garcia - Cleveland Clinic, Cleveland, USA

Prof Jorge Garcia speaks to ecancer at the 2019 International Gastrointestinal, Liver and Uro-Oncology Conference (IGILUC) in Cairo about the management of metastatic castration-sensitive prostate cancer.

Prof Garcia explains the drastic changes in the management of these patients over the past 4 years. Traditionally, the suppression of testosterone combined with sequential therapy has been the standard of care. However, in more recent times, clinicians use these agents in the first instance, rather than to wait until the patient becomes castration-resistant.

He also states the importance of investigating the 'volume of disease' in these patients, which solidified the role of docetaxel-based chemotherapy. However, data from the LATITUDE trial revealed significantly improved outcomes for men with high volume disease who were treated with ADT and abiraterone acetate.

Prof Garcia discusses data from the STAMPEDE trial in which patients with low-volume disease benefitted from ADT, abiraterone acetate and radiotherapy for the primary tumour.

 

The management for castration-sensitive metastatic prostate cancer patients has drastically changed over the last four years now. Traditionally what we do we actually block a patient’s testosterone which has been the standard of care since the ‘40s for that matter. Oftentimes what happened back in the day is once men progressed from suppression of testosterone we used to use sequential therapy, whether it’s chemotherapy or oral therapy novel agents and so forth. So what we’ve been doing over the last four years is trying to bring those agents up front because biologically it doesn’t make a lot of sense for us to wait for people to become resistant. So we did that and there were two pivotal trials in 2015 that were published, one from the British system called STAMPEDE and another one from the American system called ECOG 3805 or CHAARTED data, basically addressing the question of the role of systemic docetaxel-based chemotherapy as a frontline treatment for our patients.

In those two trials basically what we did is quite simple, we actually asked the question if we were to add docetaxel based chemotherapy to the suppression of testosterone who lives the longest? What we did, we were able to demonstrate that patients who get docetaxel based upfront actually had a significant survival improvement compared to those men who only get suppression of testosterone, what we call ADT.

Important as well is that our American data did demonstrate that benefit primarily in patients with high volume disease. So now fundamentally what I think of prostate cancer patients, fundamentally I look at volume of disease which is defined by where is your disease located and how many lesions do you have. The American data looked at very specific definitions for high volume disease which included the presence of visceral metastases, meaning lung or liver disease, and the presence of bony metastases, but specifically having more than four bone lesions and one of those had to be outside the spine, if you will. So that data in 2015, along with the British system called STAMPEDE data, actually solidified the role of docetaxel-based chemotherapy for those patients.

What changed in 2017 was the French data called LATITUDE which is the data that actually looked at the addition of abiraterone acetate, which is an oral CYP17 inhibitor, an agent capable of actually disrupting specific enzymes in the adrenal gland that are thought to be important when people become castration resistant. So LATITUDE was specifically designed for patients with high volume disease, with metastatic disease and patients were randomised to receive ADT, the suppression of testosterone, plus abiraterone acetate and prednisone against ADT plus placebo. High volume disease in the French data was defined a bit different than the American data, it was defined by you having two out of three adverse features – a Gleason score of 8, 9 or 10, the presence of more than three bone lesions, independent of where those lesions were located, and also the presence of visceral disease. So if you had two out of those three you were a high volume and you were able to enrol on trial. That trial, similar to STAMPEDE and similar to the CHAARTED data, were a powerful survival benefit and drastically we saw a significant improvement in outcome for those men who received ADT in combination with abiraterone acetate. So the hazard ratio, which is the relative risk reduction of mortality in these trials, is almost 0.6 which means you can actually tell a patient that if you get the combination of what we call intensification of your therapy with ADT and abiraterone or, for that matter, in the CHAARTED data and in STAMPEDE with ADT and chemotherapy, you can almost reduce the risk of death by almost 40% when you intensify the therapy. So now also STAMPEDE, which is the British system, also look at the addition of abiraterone for their metastatic patient population and, yet again, a significant improvement in outcome for those patients with metastatic disease.

So what has happened in the last four years since 2015 is we have reshaped how we manage men with metastatic disease. Again, people who have never seen ADT before or suppression of testosterone. So I would argue that the summary of this is that men with metastatic disease one should define their volume. If you have high volume disease the standard of care is either to get ADT plus six cycles of docetaxel based chemotherapy at the standard dose, 75mg/m2 times six cycles, followed by ADT or, if you follow STAMPEDE and/or the LATITUDE data, to give those men ADT and abiraterone acetate which are the oral agents.

That’s for high volume patients, now, for low volume patients the standard of care in my opinion, based upon the British data, the STAMPEDE data, is to offer them ADT and abiraterone acetate. What is a bit different for those low volume patients is that the British data also has very compelling data suggesting that patients who have their primary prostate in place and yet have metastatic disease and fit within a low volume group of patients, not only should they receive ADT and abiraterone acetate but also one should consider radiating the primary tumour because that is the subset of patients in that data that clearly demonstrate a survival improvement when you do ADT, abiraterone and you radiate the primary tumour. Now, it’s a bit different because the data for radiation therapy used for that matter chemotherapy in the STAMPEDE data. But we are extrapolating that data because we believe ADT chemo may be in fact similar for those patients who get ADT and abiraterone acetate.

So that, to me, has been the drastic difference over the last four years which has really reshaped how we manage these patients. So, really, a patient with metastatic prostate cancer should not be receiving ADT alone, should actually be intensified to either ADT chemo, ADT abiraterone for high volume or ADT abiraterone and maybe primary radiation therapy to the prostate tumour for low volume disease.