To recap the findings of the past decade of clinical trials in this area:
- CHAARTED taught us that docetaxel, generally given late, should be given early.
- Stampede validated this.
- Latitude showed us that abiraterone, generally given late, should be given early. Stampede validated this.
- Stampede suggested that Zoledronic acid and Celecoxib, when given to CSPC, may have an impact, but nobody listened.
- Stampede suggests that in low volume oligometastatic disease, the primary tumor should be irradiated.
What we saw in CHAARTED and Latitude was that approximately 20% of patients on androgen deprivation therapy (ADT) plus abiraterone will experience disease progression within one year, 22% will die within two years, and 33% by three years. Similarly, with ADT plus Docetaxel, 20% of patients (pts) have clinical progression after only 1 year, and about a third are dead within three years of starting therapy. As we just saw last month at ASCO, in Enzamet patients fared a little bit better, with only about 25% experiencing progressive disease within 3 years, albeit with perhaps a slight skew towards a lower volume patient population. While it is good to focus on improvements over ADT alone, which was the standard of care for, oh, about 70 years, substantial limitations still exist. The limitation is that these therapies are likely insufficient to address some mechanisms that drive eventual resistance that is present, albeit as a minute proportion of the total burden, in de novo tumors.
The biological considerations driving this lethal progression are drastically understudied. Yes, castration-resistant prostate cancer (CRPC) is extensively studied and have done a lot of work on sequencing primary tumors in an effort to predict relapse after surgery or radiation, but have we identified how and what to look at de novo metastatic tumors and how we might close the gap for that 33% who don’t experience meaningful long-term responses and benefit from upfront therapy, whether it be ADT plus abiraterone or docetaxel.
So what should we focus on?
Here's a thought – we focus on retinoblastoma tumor suppressor (Rb) loss as a molecular outcome of therapy.
I have previously written about Rb in this space in an entry entitled “Rb or not Rb, that is the question” in which I describe some of the mechanisms that an intact RB can suppress cell cycling, and how loss, or phosphorylation of Rb, can promote it. In a great recent paper published by Wassim Abida and colleagues from the Stand up to Cancer Dream team, Rb loss emerged above all other molecular aberrations as a key driver of resistance to abiraterone and enzalutamide.1
So, exactly when and how is Rb “lost”? We don’t know the second part of the question yet, but we have a sense that Rb is lost between the time of initial treatment and the emergence of resistance. In other words, it is likely intact in an untreated tumor, but in the setting of the emergence of resistance, it gets turned off or eliminated somehow.
So maybe that should be a target for our studies. What if we looked more qualitatively at the nature of the disease that is progressing compared to the one that initially appeared in the patient? For example, what if we knew Rb status in the newly diagnosed metastasis, and what if we knew that when the disease progressed, it was progressing with an intact Rb versus a lost Rb? What if we could develop a therapy that could prevent Rb loss? I think this is an important question that nobody has fully characterized. It addresses, in many ways, the boogeyman of early treatment: this idea that the problem with giving a therapy early is that when it progresses it progresses with a more aggressive phenotype. What if we characterized two distinct types of progression, progression with Rb loss (bad) versus progression with an intact Rb ( probably not as bad)? Doing so might be consistent with our overarching goal of providing clinical benefit, encapsulated in my mantra of the three P’s: Preserve (function and quality of life (QOL)), Prevent (complications, decline, and suffering ) and prolong (life).
How do we do this? We first start by collecting the data. I and my colleagues at the University of Minnesota are launching a study in July 2019 that will aim to do just that ( the study will be open at about 5 sites throughout the country through the Prostate Cancer Clinical Trials Consortium – PCCTC). For the first time in a long time, we are adding an underappreciated drug with known activity in CRPC, Carboplatin, to the ADT/Taxane/AR targeted therapy approach. In this study, called CASCARA, we are evaluating the efficacy and tolerability of ADT plus Cabazitaxel and Carboplatin followed by Abiraterone in patients with high volume castration sensitive disease.
As important as the therapy we give is what we will be doing on the correlative side. We will rigorously collect pre-treatment tissue and perform DNA sequencing on tissue that is available in addition to cell free DNA and, if available, tissue that emerges at the time of clinical progression. Although carboplatin is not specific for Rb, it is chosen because of its activity in a) neuroendocrine disease, another treatment-emergent and aggressive subtype, b) tumors with DNA repair alterations ( could early carboplatin eradicate these clones?) and c) we hypothesize that because it is cell cycle active (Carboplatin will cause DNA cross links and thus impair DNA synthesis during mitosis) it may be preferentially lethal for only the tumor clones that are in cell cycle. Those clones, as I indicated in my earlier blog, maybe the very ones that harbor Rb loss. Thus, we propose, IF progression has to happen after chemotherapy and ADT, we would prefer that it happen with an intact Rb. Doing so will lead to a better prognosis, and potentially sensitivity to another new class of therapy we are studying, the CDK4/6 inhibitor.
It’s time to think differently about Hormone-Sensitive disease. Hopefully, this is one way we can do so.
Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
Published Date: July 18th, 2019