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

PSA Numbers and How to Make Sense of Them

What should the PSA level be?  Before we look at some numbers, please note:  if a man’s PSA is higher than these numbers, that doesn’t necessarily mean that he has prostate cancer; there are other factors that can raise PSA, which we will cover briefly.  I have much more about PSA here, and of course, in the book. 

• For men in their 40s and 50s: A PSA score greater than 2.5 ng/ml is considered abnormal. The median PSA for this age range is 0.6 to 0.7 ng/ml.
• For men in their 60s: A PSA score greater than 4.0 ng/ml is considered abnormal. The normal range is between 1.0 and 1.5 ng/ml.
• An abnormal rise (the rate and speed of change in PSA is called PSA velocity): A PSA score may also be considered abnormal if it rises a certain amount in a single year. For example, if a man’s PSA score rises more than 0.4 ng/ml in a single year, he needs to find out why.  If his PSA is going up and down but is still higher than it should be, he needs to find out why.

Men: If you are in your 40s and your PSA level is greater than 0.6 ng/ml, or if you are in your 50s and your PSA is greater than 0.7, you should have your PSA measured at least every two years.  If your PSA is below this, you may be able to wait as long as five years for the next test.

In older men, benign enlargement of the prostate (called BPH) can also raise the PSA number.  BPH is very common: it’s in 50 percent of men in their 50s, 60 percent of men in their 60s, 70 percent of men in their seventies, etc.  Note:  Drugs to treat BPH can artificially lower PSA by as much as half.  Taking a 5-alpha-reductase inhibitor, such as finasteride (Proscar) or dutasteride (Avodart) to treat BPH, or the drug Propecia, used to deter hair loss (a low-dose form of finasteride) can artificially lower PSA.  If a man has been taking one of these drugs for a short period of time, his PSA number should be doubled.  If he has been taking it for five years or longer, his PSA should be multiplied by 2.5.  Don’t just take that low score at face value.

Here are more PSA numbers from the book,, adapted from the Journal of the American Medical Association:

How many men my age have this PSA level?

2.5 or lower:  88 percent of men in their 50s, 75 percent of men in their 60s, and 61 percent of men age 70 or above.

2.6-4.0:  8 percent of men in their 50s. 14 percent of men in their 60s, and 18 percent of men age 70 or above.

4.1-9.8: 3 percent of men in their 50s.  9 percent of men in their 60s, and 16 percent of men age 70 or above.

10 or higher:  1 percent of men in their 50s.  2 percent of men in their 60s, and 5 percent of men age 70 or above.

All of this said, a PSA score on its own is not enough, because other things can raise PSA.  This is why getting that baseline and then watching what PSA does over time is so important.  This is PSA velocity:  watching what PSA does.

What else can raise PSA?

             Here’s a tip:  Get the PSA blood test done before the rectal exam at the annual physical.  The rectal exam, when the doctor pokes the prostate to check for any signs of hardness or lumps, can cause PSA to be released into the bloodstream – artificially raising the PSA number.  (Fun fact: what’s the prostate supposed to feel like?  Feel the pad at the base of your thumb.  The prostate should feel kind of squishy like that.)

            Similarly, so can having sex.  Therefore, a man should avoid sexual activity for three days before the blood test.  

Prostatitis can also raise PSA, sometimes to high levels.  This is not cancer; it’s inflammation in the prostate and it is treatable.  I have good information about prostatitis and pelvic pain syndrome here.

Second-Line Tests Shed Light in the Darkness!

Fortunately, there are “second-line” blood and urine tests that can help figure out if a raised PSA number is coming from BPH or prostate cancer.

I’ve got much more about these tests here, but briefly:  Nuanced tests such as the 4K score or Prostate Health Index (PHI) look at “free PSA.”  PSA comes in several different forms.  Free PSA measures whatever PSA in the blood that is not bound to proteins.  As Johns Hopkins urologist H. Ballentine Carter, M.D., was fond of saying, the higher percentage of PSA that is free, the more likely you are to be free from cancer.  This test provides context:  If the percentage of free PSA is higher than 25, then the elevated PSA is more likely to be caused by BPH, benign enlargement of the prostate.  If it’s lower than 25 percent, this doesn’t automatically mean that there’s cancer, but it does raise the likelihood that cancer may be present.  The 4K and PHI tests are even more helpful than the free PSA test, because they also look for biomarkers of aggressive cancer, and put it all together into a score.

What if these things point to cancer?  Is the next step biopsy?  No, it’s prostate MRI.

I’ve written about that here, but basically, the result of prostate MRI is called a PI-RADS score, ranging from 1 to 5.  A PI-RADS score of 3 or higher is the trigger for a biopsy.

That biopsy should be an MRI fusion biopsy, where the MRI image is combined with transrectal ultrasound to give the doctor the best view of any suspicious areas that really need to be checked.  In the biopsy, 12-14 hollow-core needles are used to get samples, or cores, of tissue.  Note:  a biopsy is not perfect; each needle only samples 1/10,000^th of the prostate!  In the book I’ve said it’s like looking with a needle in a haystack.  That’s why the second-line tests can help paint a more complete picture of what’s going on in the prostate.

            There are two ways to have the biopsy done:  through the rectum (transrectal) and through the perineum, the area of skin between the rectum and the scrotum.  If you think of the prostate as about the size of a golf ball, the transrectal approach basically goes from south to north.  The transperineal approach goes from east to west, and it does a much better job of finding out-of-the-way cancer.  I’ve written about that here.  Not only is it more effective:  there is zero risk of infection.  No need for antibiotics!  It’s also better for diabetic men, who are at higher risk of getting an infection.  The transrectal approach, because it goes through the rectum, involves antibiotics.  There’s no getting around it; the rectum is chock full of bacteria.  Transperineal is the better way to go.

Since this series is about screening and detecting cancer, I’m going to leave it here and not get into treatment.  That is covered throughout this website, and if there’s interest, will be the subject of another series.  Very briefly, if cancer is found, you will be given a Gleason score, or Gleason grade group.  The cancer can range from very low, low, and favorable intermediate risk – which may not ever need treatment – to unfavorable intermediate, high, and very high risk.  You will also be given a clinical stage, which is the estimate of how much cancer there is – whether it is confined to the prostate (the most common scenario in the U.S. today because of screening); whether it has spread locally but does not appear to be present at distant sites (seen with imaging); or rarely, less than 10 percent of the time, whether the cancer has spread to either the lymph nodes or bone.  Whatever the finding, don’t become discouraged!  There is more hope now than ever before.

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

Recently, I gave a talk on what women need to know about prostate cancer.  It was supposed to be for 20 minutes, but it went on for well over an hour because the ladies, ranging from their 30s to 70s, had so many questions.  So…Ladies, this one is for you.  Actually, it is for men in their 40s and 50s, but they probably won’t read it. 

I can attest that this is true.  My own dad, diagnosed in his early 60s with prostate cancer and cured by Johns Hopkins urologist Patrick Walsh, M.D. (my longtime co-author of now seven books on the subject) never read our book. Instead, my mom read it to him, passages she had previously highlighted, as they drove up I-95 from South Carolina to Baltimore for the surgery that saved his life and enabled him to live 20 more years.  In fact, my mom and I were the ones who made him start getting his prostate checked in the first place, something he definitely did not want to do.

When my husband, Mark, at age 59 found out that his PSA went up from a 2.0 – which I had thought was high and was watching it – to a 3.0, and his local doctor said it was “still low and in the normal range” (this was garbage; we disproved this in our books in the early 2000s), I recommended a second-line blood test (see Part 3) for clarification.  When that suggested cancer, I said:  “You need an MRI and a biopsy.”  He wasn’t convinced, and his local doctor said he could wait a while and see (really bad advice).  I called Pat Walsh, who not only told Mark the same thing, but told him which doctors he had picked out to do the biopsy and the surgery.  Thank God we got it when we did, and Mark is now cancer-free.  You can read Mark’s story here.

I have several key points for you to consider:  One, the younger men who are most likely to be cured of prostate cancer or, if it is slow-growing, followed carefully in active surveillance, are the least likely to be checking for it. ***Note***If a man is already getting PSA testing and wants to know more about the numbers, jump right to Part 3.***

Two, for whatever reason, more people are being diagnosed with cancer at a younger age.  You can take your pick on the reasons, and I have some thoughts, but the point is simply that it’s happening, and younger men need to start getting checked.  Because prostate cancer, when caught early, is 100 percent curable.

Three, despite what your family doctor may say, men need a baseline PSA blood test starting at age 40.

It’s just a simple blood test.  We will talk more about this in Parts 2 and 3.  (Personal note, because we have a high-risk family with six men affected so far on both Mark’s and my sides, I am going to make my sons get a baseline test at age 35.)  Also, we will talk about what the PSA numbers should be, and about more specific, second-line blood tests that can help determine if it’s cancer.  Please keep reading!

Four, treatment for prostate cancer is better than ever.  And, a diagnosis of prostate cancer doesn’t always mean that a man needs to be treated right away.  Many men can be treated for years or even indefinitely with active surveillance: they are followed carefully, and then treated only if and when the cancer starts to progress.  If a man does need treatment, surgery and external-beam radiation therapy are better than ever.  And: new advances suggest that in the next few years, we will see more and more focal therapy (treating only the cancer within the prostate, not removing the whole prostate), and even partial prostatectomies (like a lumpectomy for breast cancer).  We’re not there yet, but with better imaging and with in-surgery use of tracers such as the PSMA-targeting radionuclides, which can light up tiny spots of cancer invisible to the naked eye in PET imaging, it will be possible during surgery to know which tissue can safely be spared.  This should help minimize side effects of temporary urinary incontinence and ED.  Where surgery goes, radiation goes, as well, and I predict more nerve-sparing forms of radiation therapy and even more highly targeted therapy that will minimize side effects, too.

Step one: Get the baseline PSA.  Ideally, at age 40, but in the 40s is better than waiting until age 50.  (However, if a man is in his 50s and hasn’t had a PSA test, he needs to get one!)

            Note:  This is not a “one and done” thing.  What happens next depends on the number.  If a man’s PSA is lower than 1 ng/ml, the doctor may say he can wait two to four years for the next one.  However, if the man is at high risk for prostate cancer – if he has a family history of cancer and/or prostate cancer, or if he is of African descent – he should just get on the PSA train and get screened every year.

            Here’s something to think about:  A lot of men don’t know their family history.  So how do they know if they are at higher risk of getting prostate cancer?  Also, for many people, including our family, the family history changes in real time.  When Mark and I got married, we didn’t have any prostate cancer in the family.  Then his dad died of it at age 53, his maternal grandfather died in his 80s of complications from radiation that he probably didn’t need, my grandfather died in his 80s of complications from estrogen (they don’t even use that now) that he probably didn’t need, either.  Then my dad got it.  Then Mark, and then his paternal uncle.  So we’re six and counting.  But again, we weren’t a prostate family… until we were.

Next:  Part 2:  Why is PSA Screening Such an Issue?

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