Steph’s Note: Sure, I know a lot of you are looking at that title thinking, “I’m not (going to be) a hem/onc pharmacist, and that sounds way too in depth for me.” But before you decide to go Netflix instead of reading this fantastic post, hear me out. At some point in your pharmacy career, you will encounter a patient who has (or has had) prostate cancer. And I’m willing to bet you’ll see these therapies on a medication list or in your verification queue. So don’t be hasty, and read along!

Our friend, Christie Baker, is back this week to make prostate cancer therapies just a little more approachable. You may remember her from this previous professionally-minded tl;dr post, but this time’s she’s here to drop some clinical knowledge in addition to her professional experience. Teach us, Christie!

In general, they say things get finer with age - wine, cheese, anything leather, and friendships. Unfortunately, the human body isn’t typically one of those things. Even the best machines tend to break from wear and tear over time, and the prostate is no exception.

This cat understands the waiting it out game. Hunker down, get comfy, and just…chill. (Image)

The Basics of Prostate Cancer

Prostate cancer is a slow-growing disease that generally comes with age. In fact, it’s so slow that patients who are asymptomatic, in lower risk groups, and/or have shorter life expectancies are often treated with the “watch and wait” approach because maybe we can just wait the darn cancer out.

Think about it… If it’s not bothering you or you aren’t going to live long enough to reap the benefits, why waste the time and money, and why risk the potential negative impact on quality of life?

So exactly how is this slow-growing cancer classified?

There are 4 stages of prostate cancer: early (stages I and II), locally advanced (III) and advanced (IV). The stages are defined by the Gleason Score and the standard TNM Score.

In short, the Gleason score is based on the architecture of the prostate tissue and how it changes when transitioning from normal to cancerous. You may have heard of the TNM Score as it is used for many different types of cancers. It refers to the characteristics of the primary Tumor, the number of nearby lymph Nodes affected, and whether the cancer has Metastasized. So these scores define the stages of prostate cancer, which you can generally think of as follows:

Early: confined to prostate
Locally advanced: spread to nearby tissue
Advanced: spread further than nearby tissue

Let’s talk about a couple more definitions that are important to know in order to grasp the drugs we are going to look at in a bit. First, there is castration-sensitive prostate cancer (CSPC), which is the most responsive to therapy. This term just means that we are able to control the cancer by keeping testosterone at castrate level (<50 ng/dL).

Unfortunately, advanced prostate cancer isn’t curable. Once the cancer decides it can grow without testosterone, we reclassify it as castration-resistant prostate cancer (CRPC). We can determine whether a patient has CSPC versus CRPC using labs. When prostate-specific antigen (PSA) levels start rising despite low testosterone levels, that’s a red flag that the patient has transitioned to CRPC.

If the cancer spreads beyond the prostate to other organs, bones, or lymph nodes outside the pelvis, the cancer is then considered metastatic...so mCSPC or mCRPC. An “nm” prefix means non-metastatic.

Alright, with the definitions and acronyms out of the way, next up let’s discuss how we treat prostate cancer - if and we when need to.

Treatment for Prostate Cancer

When we DO decide to treat prostate cancer rather than playing the waiting game, there are 4 main treatments: radiation, surgery, androgen deprivation therapy (ADT), and non-hormonal systemic therapy. (I’m not going to discuss the non-hormonal therapies here because that’s a post in and of itself, and this is tl;dr.) Since this is a pharmacy website, my little fireside chat is going to focus mainly on the medications involved in ADT, but still, a general understanding of the other treatments is important for understanding ADT’s place in the treatment scheme.

Radiation Therapy for Prostate Cancer

Radiation is recommended in combination with ADT because it can reduce the duration of treatment, and who wouldn’t want that?!

The two main kinds of radiation are external beam radiation therapy (EBRT) and brachytherapy. EBRT is the kind of radiation you normally think about, whereas brachytherapy is implanted radiation, which is usually used in combination with EBRT as a booster.

Implanted radiation, what??!?

Brachytherapy is used in many different cancers, but in the case of the prostate, little radioactive rice-sized seeds are inserted into the prostate to release low-dose radiation over many months. Just like with our targeted therapies, brachytherapy causes less damage to the surrounding tissue because it is more localized. The whole point of radiation is to stop cell division and therefore stop cancer.

If interested in the radiation world, I’d recommend reading up on radiopharmaceutical therapies. (Yes, it says –pharmaceutical… but no, pharmacy is not really involved. In fact, we cannot even store these drugs in the pharmacy!) These drugs are reserved for the metastatic setting with Lu-177–PSMA-617 being the new kid on the block.

Surgery for Prostate Cancer

This’ll be brief. There are a couple options…

Prostatectomy: remove the prostate when the cancer is still localized (only in the prostate)
Radical prostatectomy: remove the prostate and surrounding lymph nodes
Orchiectomy or surgical castration: remove one or both testes as an option for androgen deprivation therapy, which leads us to the main event…..

Androgen Deprivation Therapy (ADT) for Prostate Cancer

So what is this ADT? (Not the security system. That’s for another website).

For our purposes, it’s pretty straight-forward. Androgens, including testosterone, fuel prostate cancer. Stop androgens = shrink or slow prostate cancer.

Androgens come from the testes (why orchiectomy is a surgical component of treatment), the prostate glands (why prostatectomy and radiation work), and the adrenal glands. It’s important to recognize that ADT alone does not cure prostate cancer, but when used in combination with radiation and/or surgery, it can keep cancer at bay.

Now can you see why we needed to talk about radiation and surgery at least a little bit? Soooo let’s get to the drugs!

LHRH Agonists for Prostate Cancer ADT

Luteinizing hormone-releasing hormone (LHRH) agonists cause testosterone decrease due to stimulation of LH and FSH.

How? Think back to reproduction class. If you have high amounts of LH, then your body thinks it has too much testosterone. So although there is an initial surge, testosterone levels subsequently become so low due to the negative feedback loop that it is considered a medical castration – castration without the blade.

Really, for all of these treatments that decrease testosterone, the most common side effects include hot flashes, decreased libido, erectile dysfunction, loss of bone mineral density, anemia, and mood changes.

Basically, what you would expect with low T.

As discussed above, starting these LHRH agonists leads to an initial bump in testosterone levels. This can actually lead to a tumor surge or flare, in which the prostate cancer cells thrive and grow more. It actually feeds the cancer exactly what it wants! For the patient with metastatic prostate cancer, this can mean bone pain, trouble urinating, and spinal compression… But there are also some recent thoughts that this testosterone surge and subsequent cancer cell mitotic activity are what allow concomitant radiation therapy to work so well. Sooo hmm, confounding!

First Generation Antiandrogens for Prostate Cancer ADT

First generation antiandrogens are competitive inhibitors of testosterone and should definitely be considered in the metastatic setting. When used in combination with LHRH agonists or orchiectomy, it is called combined androgen blockade (CAD).

These drugs alone cannot block testosterone production and so are used in combination with LHRH agonists to prevent T flares. Often these medications are started a couple weeks before an LHRH agonist and continued for various periods of time. The side effects are similar to LHRH agonists with hot flashes, decreased libido, and impotence but also increased diarrhea and gynecomastia.

Bicalutamide is seen a lot in practice, but it has by far the longest list of side effects and interactions. Male patients need to be counseled on the use of effective contraception during therapy and for a bit after the last dose (up to 130 days with bicalutamide!).

First generation antiandrogen medications used for prostate cancer ADT.

Androgen Receptor Inhibitors for Prostate Cancer ADT

Androgen receptor inhibitors, or newer antiandrogens, have better binding than the first-generation antiandrogens and have actually been shown to impact overall survival. Like the first generation medications, male patients need to be counseled on the use of effective contraception during therapy and for up to 3 months after the last dose, depending on the specific medication used.

All of these drugs carry seizure and cardiovascular disease risks. Additionally, and get ready for the direct to consumer advertising side effect voice here, fatigue, pain, hyperglycemia, hypertension, hot flashes, constipation/diarrhea, decreased appetite, and rash are all associated with these drugs. Lovely. FYI, for what it’s worth, fatigue may be the best with apalutamide, but that can vary.

Clinically, pain is a super big deal in this class as it may be an indicator of efficacy. Make sure that these patients are getting effective pain management because it’s hard to keep our guys on these drugs if they have poor control over pain.

The newer antiandrogens for prostate cancer ADT.

The strangest thing about the antiandrogen class is the antiandrogen withdrawal syndrome. This has been studied more with the first generation medications, but there are more and more studies looking into the newer generation drugs as well. The mechanism hasn’t quite been worked out yet, but many patients with higher prostate-specific antigen (PSA) levels experience decreasing PSA values and clinical improvement for weeks or months after stopping an antiandrogen!

A withdrawal syndrome that has positive effects? Well I’ll be… pleasantly surprised. (Image)

As a pharmacist, this is an important phenomenon to be aware of when switching therapies or enrolling in clinical trials as these effects could be misattributed to a new therapy when in fact the benefits could be the result of withdrawing the previous therapy. So odd!

LHRH Antagonists for Prostate Cancer ADT

LHRH antagonists take a more direct path to testosterone-lowering by just plain stopping the LHRH. Unlike the LHRH agonists, which rely on the roundabout negative feedback loop to decrease testosterone production, the antagonists don’t typically cause the tumor flare. But the other side effects are pretty similar.

As expected from this direct inhibition, we usually see a more rapid reduction in testosterone levels. In fact, the use of an antiandrogen is generally not recommended.

LHRH antagonists for prostate cancer ADT.

Abiraterone for Prostate Cancer ADT

Abiraterone is going to be the last drug we cover in this talk because frankly, this is a long post, and you’re probably tired of reading about the prostate at this point. Remember at the beginning of this ADT section, I talked about the different places androgens come from?

Abiraterone irreversibly binds to CYP17, which is required for androgen creation in the testes, prostate, AND adrenal tissue. Because it has activity in the adrenal tissue, steroids must be given to prevent adrenal insufficiency. Increased dosage of corticosteroids may be indicated before, during, and after stressful situations to prevent adrenal insufficiency as well.

On the flipside, we also have to look for mineralocorticoid excess, which means monitoring blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

If you remember nothing else from this section, keep this in your brain: AVAILABLE ABIRATERONES ARE NOT THE SAME DRUG.

Yes, they are both abiraterone, but they’re different formulations and actually carry different indications. The most common side effects are fatigue, aches and pains, hypertension, edema, hot flushes, nausea/vomiting/diarrhea, hypertriglyceridemia, hypercholesterolemia, hyperglycemia, anemia, and hypokalemia. Geez, another commercial list. I can hear the voice now.

Since steroids also can cause hypertension, edema, and hyperglycemia, we really need to be vigilant about counseling those with related comorbidities who receive combination therapy with abiraterone. Those struggling with fatigue may benefit from evening dosing, but that gets a little hard with the standard formulation since it has to be on an empty stomach.

The 2 formulations of abiraterone, which are NOT the same.

The tl;dr of Androgen Deprivation Therapy for Prostate Cancer

So the tl;dr for androgen deprivation therapy is DEPRIVE TO THRIVE. We need to get the testosterone fuel source for prostate cancer to levels less than 50 ng/dL, and we can get there with our multimodal approach to treating this unfortunately common cancer. This is by no means an all-inclusive list for prostate treatment since I didn’t even hit on the systemic non-hormonal treatments, but this should get you started!

Deprive to Thrive: An Introduction to Androgen Deprivation Therapy for Prostate Cancer