Many studies have shown that hitting prostate cancer hard in early metastasis with more than one treatment approach minimizes symptoms, preserves quality of life, and prolongs survival. So why aren’t more men being offered the standard of care?
What is undertreatment? It’s aiming too low: undershooting the arrow and falling short of the target, or bringing the proverbial knife to the gunfight. It is inadequate, and if you have mHSPC (metastatic hormone-sensitive prostate cancer, or early metastasis, when the cancer still responds to hormone therapy) and are otherwise in fairly good health, this is what you should avoid.
Unfortunately, undertreatment is the word that best sums up what is happening to thousands of American men with early metastatic prostate cancer. This is bad news, but it’s also good news: bad news, because many men are not receiving the standard of care for mHSPC. Good news, because this is a fixable problem! Better treatment is available today, it’s covered by Medicare and most insurance, and newly enacted legislation will make this care even more accessible.
When it comes to treating mHSPC, “more is more,” says medical oncologist Neeraj Agarwal, M.D., of the University of Utah’s Huntsman Cancer Institute, an internationally recognized physician-scientist in the field of prostate cancer and the management of metastatic disease. Specifically: ADT (androgen deprivation therapy, also known as hormone therapy. It dramatically lowers the male hormone testosterone, which is a driver of prostate cancer—see box below) alone is not enough. “The standard of care is combination therapy.” This means ADT plus something else: total androgen blockade with an androgen-receptor pathway inhibitor (ARPI).
This is a kitchen-sink approach, rather than a “let’s try this, and if it doesn’t work, let’s try this other approach.” Not so many years ago, treatment of metastatic prostate cancer used to be like navigating a boat through a series of channels. Plan A was ADT. Then, only after the cancer progressed, men moved on to Plan B and then Plan C, with an ARPI and then chemotherapy, or vice versa.
The Standard of Care Has Changed
In 2015, the first of a series of envelope-pushing studies was published and the treatment approach began to broaden. What would happen if, instead of waiting for ADT to fail, we tried to prolong its success? What if we started giving these next-step options sooner? Landmark clinical trials* showed the success of giving combination therapy up front in early metastasis. The initial trials compared ADT plus docetaxel vs. ADT alone; subsequent trials showed even more promising results comparing ADT plus an ARPI vs. ADT alone. The results were so striking that combination therapy is now the standard of care.
Which ARPI is best? “That’s never been compared,” says Agarwal, “but most patients will be doing well on any ARPI they get along with ADT. If you look at the results of these studies, it’s striking to see that every single ADT plus ARPI regimen showed about a 30- to 40-percent reduction in the risk of death. Some men can live for many years. We know that ADT plus an ARPI is a potent combination. Based on the data, we should try to get combination therapy to all patients with mHSPC.” The only exceptions, Agarwal adds, are men with other serious health problems who do not have a life expectancy beyond two years. For these men, ADT alone is sufficient, “but that’s a very small number of patients.”
The National Comprehensive Cancer Network (NCCN)’s guidelines for men with mHSPC were updated in 2023 to recommend doublet (ADT plus an ARPI) and even triplet therapy (ADT plus both additional approaches) up front. In addition, for selected men NCCN recommends external-beam radiation to the prostate if there are just a few metastases, also known as low-volume disease.
“Just a decade ago, the median survival for men with mHSPC (who were first treated with ADT alone) was 32 to 36 months,” says Agarwal. (Note: this means that half of the patients died by this time.) “When docetaxel was moved to the frontline setting (being given along with ADT early on), that improved survival significantly. When ARPIs – enzalutamide, abiraterone, apalutamide, darolutamide – were used early on, they all showed very similar efficacy. They delay hormone resistance and the symptoms of metastatic prostate cancer – fractures, bone pain, and death – and this dramatically improves overall survival without compromising quality of life. We do all of that when we use these therapies up front.”
But wait – I’m on ADT Alone! Is it too late for me to start combination therapy?
No, it is not! If you are a patient newly diagnosed with mHSPC, talk to your doctor about combination therapy. If you have mHSPC and you’re only on ADT now, it’s not too late! Talk to your doctor about adding an ARPI with or without docetaxel now.
*These landmark trials and publications included CHAARTED, LATITUDE, STAMPEDE, TITAN, ENZAMET, and ARCHES.
It’s Alphabet Soup! Making Sense of All these Abbreviations
ADT stands for androgen deprivation therapy. Androgens are male hormones, and the primary male hormone is testosterone. ADT (drugs like leuprolide and degarelix) shuts down testosterone. However…
Prostate cancer is sneaky! It can start making its own bootleg androgens. This is why a total androgen blockade — getting rid of all androgens — is a more thorough approach, one that has been shown in numerous landmark studies to work better than ADT alone.
Androgen blockade is best achieved with drugs called ARPIs, for androgen receptor pathway inhibitors. This fairly new class of medicines includes enzalutamide, abiraterone, apalutamide, and darolutamide. (You may also see these referred to as AR-blocking drugs.)
There are also abbreviations for metastatic prostate cancer itself. One big problem with prostate cancer is that it is heterogeneous; it’s a mix of many different types of cells. Most of these cells respond to hormone therapy, but not all of them do. Over time, the cells that don’t respond to hormone therapy can outnumber the ones that do respond to it.
Early metastasis is called mHSPC, for metastatic hormone-sensitive (vulnerable to hormone therapy) prostate cancer.
Later metastasis is known as CRPC, for castrate-resistant (no longer responding to the lack of testicular testosterone) prostate cancer. However, some doctors call this HIPC (hormone-independent, or -insensitive prostate cancer).
Up next: Part 2: Why Aren’t More Men Getting Combination Therapy?
