Don’t Undertreat Metastatic Prostate Cancer!  Part 2

Roadblocks to Combination Therapy, and Paving the Way for Success

            As we discussed in Part 1, the year 2015 was a milestone in treatment of early metastasis (metastatic hormone-sensitive prostate cancer, or mHSPC).  For the first time, the CHAARTED study showed that men with mHSPC who began ADT (androgen deprivation therapy, which shuts down testosterone) plus chemotherapy (docetaxel) lived significantly longer than men who started treatment with ADT alone.

This study was the first of several that changed the standard of treatment for early metastatic prostate cancer to combination therapy:  ADT plus docetaxel or ADT plus an androgen-receptor pathway inhibitor (ARPI; these drugs include enzalutamide, abiraterone, apalutamide, and darolutamide) or ADT plus chemo plus an ARPI.

With combination therapy, median survival – again, some men live much longer – is now about five years, compared to around three years a decade ago.  The results continue to improve as new drugs are developed and doctors keep pushing the treatment envelope.  This improvement is monumental, says medical oncologist Neeraj Agarwal, M.D., of the University of Utah’s Huntsman Cancer Institute.  I recently interviewed him for the Prosate Cancer Foundation’s website.   It’s particularly so, he continues, “when you consider that some anticancer drugs get approved based on a three-month survival benefit.  There is no doubt that ADT alone is not sufficient.  It works so much better when it is combined with one of these ARPIs.”

And yet.  This is not the case for thousands of American men with mHSPC, Agarwal states:  “A lot of patients in the U.S. – the richest country in the world – are not getting ADT plus ARPI  or ADT plus ARPI plus docetaxel, up front.  That is unacceptable in our view, because of the significant survival advantage and quality-of-life benefits associated with combination therapy.”

 What is the problem?  Unfortunately, there are several.

“There is no shortage of evidence that combination therapy works,” says Agarwal.  However, “the number one reason that combination therapy is not being used up front in patients with mHSPC is lack of awareness of the data.”  A lot of clinicians have a pre-2015 mindset about mHSPC.  “They fear that if you use everything up front, what will you use later?  They want to keep these therapies for the time when ADT fails.”

But here’s the thing:  using both therapies up front may significantly delay or even change the course of mHSPC. Nobody really knows; there have been no long-term studies because this standard of care is still too new.  However, in my experience of studying and writing about prostate cancer over the last 30 years, I will tell you that all of the things that used to be done as a last resort have done much better when used as weapons against prostate cancer sooner rather than later, when cancer is more vulnerable.  We’re not there yet, in terms of being able to put all men with prostate cancer into a durable remission, but that is the goal.

Agarwal is the senior author of a striking study published in 2023 in the Journal of Urology, looking at how physicians in different specialties treat men with mHSPC.  “We found that combination therapy was underused as a first line of therapy across urology and oncology specialties despite evidence of improved survival,” he says. “In subsequent lines of therapy, ADT plus ARPI was prescribed more frequently across specialties,” but these men would have been better off if they had hit mHSPC with both barrels from the start. 

“We found that many physicians are worried about the side effects of these medicines,” says Agarwal.  “In a lot of medical oncology practices, doctors are dealing with many different types of cancer in a given clinic, so do they have enough time to delve into prostate cancer only?  On the other side, many urologists are very busy surgeons.  How much time do they have to spend on learning about the latest data?  Misconceptions happen because of lack of awareness.  They think, ‘these drugs have toxicities; we need to keep them for later.’  They’re not aware of the data; that’s why they have these misconceptions.”

But it gets more complicated.  There are financial roadblocks, as well.  In our  country, medical care in general is expensive and complicated, and many medical practices rely heavily on a small team of people whose job is simply to be on the phone with insurance companies every single day, advocating for patients.

“Using combination therapy is associated with more workload for clinicians and their practices,” says Agarwal, “especially if you don’t have enough support staff.  Many solo oncology practices don’t have the support of an in-house nurse practitioner, pharmacist, or big team of financial people who can write letters or talk on the phone with insurance companies.”  There are copay issues with combination therapy, he continues, and also issues arising from comorbidities – other health problems requiring other drugs that may interact with one ARPI versus another.

Here’s an example:  “Eliquis (a blood-thinning drug) is quite common.  But it has an interaction with enzalutamide.  You either have to talk with a primary care doctor or cardiologist to see if you can have Eliquis switched to something else, or you have to fight with an insurance company to switch to abiraterone or darolutamide if they have enzalutamide as their preferred agent.”

With insurance and also with Medicare, out-of-pocket copays are a big problem for many patients.  One option for the man on Eliquis might be abiraterone, which has another major benefit:  Abiraterone has been around long enough that it has “gone generic,” and is much less expensive than other ARPIs.  “This man could get abiraterone for $170 a month.  But many patients have zero copay for enzalutamide; it’s $15,000 per month, but their copay is zero.”  If this man only has Medicare, “and he doesn’t have a backup insurance plan to help with the out-of-pocket costs, it can be very challenging to afford that monthly copay,” which could run into the thousands each month, depending on a patient’s insurance plan, and whether he – not to mention his spouse or partner – is on any other expensive medications.

What about a coupon?  Unfortunately, coupons don’t always help, Agarwal continues.  “Say you have a coupon from a pharmaceutical company for $200 for your copay.  That is not considered by the insurance company as support for the copay.  Instead, it’s considered as a contribution toward the base price of the drug, which is wrong.”

It sure is.  Agarwal has been advocating on Capitol Hill for legislation to help relieve the financial burden for patients with cancer.  The recent Inflation Reduction Act contains a provision that allows Medicare to negotiate the price of some prescription drugs.  Additionally, “patients on Medicare will have a $2,000 yearly cap on out-of-pocket prescription drug costs, starting this year,” says Agarwal, “so that should help.”

Maximize Your Odds for Success

Here’s something Agarwal always tells his patients before they start combination therapy:  “Yes, you will feel overwhelmed, because your life has changed.  But I have a lot of patients who are living for years – beyond a decade  – and I give them this hope:  You could be one of them.”

            Just as the best way to target early metastasis is to hit it hard, right from the beginning, the best way to approach combination therapy is to address all of its potential side effects right up front.

The drugs can take a toll, says Agarwal.  “There’s fatigue, loss of muscle mass, the risk of metabolic syndrome, increased fat around the midsection, increased cardiovascular risk, increased risk of stroke, quality of life issues – hot flashes, inability to perform your daily duties to the max, and the effect of treatment on your marriage and romantic life.  But there are ways to handle all of this.”

            Here are some key points for doctors and patients to consider:

            Exercise:  cardiovascular exercise with resistance training “is more important than ever.”  Agarwal is principal investigator of a NCI-funded study that starts combination therapy patients on a yearlong exercise program.  As we have discussed, for men with mHSPC, any exercise is better than none, and even light weights and short bursts of exercise can make a big difference.

            Taking care of the heart:  “Screening for cardiac issues is more important than ever, too, says Agarwal.  When he starts patients on ADT plus an ARPI, “it’s routine for me to do EKGs in my clinic, especially in those patients who seem to be prone to cardiac disease.”  These include men who have a history of smoking, or who are overweight or who don’t have a very active lifestyle, or who feel short of breath.  He works with cardiologists and family physicians to make sure the patients get a stress test, cholesterol and other blood tests, or other workups if needed.

             Taking care of the bones:  “So many times this is missed,” Agarwal says.  “If somebody already has low bone density and then starts on ADT and an ARPI, he will start having fractures.  Vitamin D, and calcium plus exercise really go a long way to help strengthen the bones. We recommend bone-modifying agents to those who have thin bones to start with.”  Diet can help here, as well:  leafy green vegetables are really good for the bones.

             Social help can be huge:  “It takes a village, especially in the early days,” says Agarwal.  “I tell my patients, ‘You need to get over this immediate barrier, these seemingly insurmountable barriers of tests, medications, and insurance – so let’s work together.’  That’s why a social worker and financial counselor play such big roles in the beginning.”

            And then… “These same patients, their insurance resolved, all the screening done, the combination therapy begun – their PSA has dropped.  They are feeling great.  They don’t have pain, they’re feeling much better.  They come back and say ‘Thank you very much.’  After six months, their whole family has a sense of relief.  Those first three to four months are crucial.  And then, after six months, I really hope we can say we did it together.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.  Note: I am an Amazon affiliate, so if you do click the link and buy a book, I will theoretically make a small amount of money.  

© Janet Farrar Worthington