Understanding the Standard Playbook

CHAPTER 2 Understand the Standard Playbook

 

This is the longest chapter in this guide because it holds the most ground: how your disease gets staged, the single concept that explains almost every treatment decision you will face, and the actual drugs and pathways used to treat metastatic prostate cancer today.

The NCCN Standard of Care for Prostate Cancer

The National Comprehensive Cancer Network (NCCN) publishes evidence-based guidelines that most oncologists follow. The current version is NCCN Prostate Cancer Version 5.2026. The patient-friendly version is available at nccn.org/patients. This is the playbook your urologist and oncologist will use to plan your care.

FDA-Approved Workup and Diagnosis

• PSA blood test: The starting point. Trend matters more than a single number.
• mpMRI of the prostate: Now Category 1 NCCN evidence before biopsy. A PI-RADS score of 3, 4, or 5 raises suspicion and helps target the biopsy, minimizing risks of an inaccurate workup.
• MRI-targeted biopsy: When suspicious areas are seen on mpMRI, biopsy is done using fusion technology to target those exact spots, as well as to sample the rest of the gland.
• Artera AI Prostate Test: A multimodal AI test that reads biopsy slides alongside clinical data to help predict which men benefit most from added hormone therapy with radiation.
• PSMA PET/CT: The current gold standard for finding metastatic disease early. It can see spots that a bone scan or CT completely miss, especially when PSA is between 0.5 and 10. Ask specifically about this scan if a bone scan or CT come back clean but your doctor is still concerned.
• Fluciclovine (Axumin) or choline PET: Alternative PET tracers used when PSMA PET is not available. Less sensitive than PSMA PET at very low PSA.
• Sodium fluoride (NaF) PET: Very sensitive for bone, but can trigger false alarms from arthritis or old injuries, so results need a doctor’s interpretation.
• Bone scan (technetium-99m) and CT scan: The traditional way to look for bone spread. Its real weakness is that it is much less reliable when PSA is under 10, so a clean bone scan at a low PSA does not fully rule out disease.
• CT scan: Looks at lymph nodes and organs. Shares the same low-PSA blind spot as a bone scan.
• Spinal MRI: Not optional, and not something to schedule for next month, if you have new back pain that is severe, worse lying down, or comes with leg weakness or numbness.
• Germline genetic testing: Now strongly recommended for any high-risk, very-high-risk, regional, or metastatic prostate cancer. Looks for BRCA2, ATM, CHEK2, BRCA1, PALB2, and Lynch syndrome genes.
• Tumor genomic profiling: Tissue or blood-based NGS testing. Critical for advanced and metastatic disease.
• Predictive Molecular Assays: Many brands (e.g., Oncotype, Decipher, Prolaris, etc.) but all have similar data. Important information to help predict the risk of extra-prostatic spread.
• Baseline labs: CBC, CMP, testosterone, vitamin D, lipid panel, A1c, and bone density (DEXA) before starting any hormone therapy.
• AUA/IPSS urinary symptom score: A short questionnaire about how often you urinate, whether you feel empty afterward, and how your stream starts and stops. Get this baseline before any treatment. It helps predict how you will do afterward, and in men with an enlarged prostate, surgery can sometimes improve urination rather than worsen it.
• Urodynamic testing: A more detailed study of bladder and sphincter function, usually reserved for men who already have urinary symptoms. Gives your team a clearer baseline before deciding between surgery and radiation.

Where This Data Actually Comes From: The Partin Tables

The risk groups below are not a guess. They come from something called the Partin Tables, built at Johns Hopkins with Dr. Alan Partin and Dr. Patrick Walsh. Researchers tracked the outcomes of roughly 40,000 men who had their prostates removed, over more than 30 years, and looked at which factors actually predicted whether cancer had already spread beyond the prostate.

No single predictor is 100% reliable. Three numbers turned out to matter most: your PSA, your Gleason score, and your T-stage (whether your doctor can feel the tumor on exam). Those three numbers, run through decades of real outcomes, are what your risk group is built on. It is one of the most data-driven parts of this entire field, and it is why a Data G takes these numbers seriously.

NCCN Risk Groups

RISK GROUP	WHAT IT MEANS
Low Risk	PSA less than 10, Grade Group 1 (Gleason 6 or less), stage T1-T2a. Note: NCCN removed the “very low risk” category in 2026.
Favorable Intermediate Risk	PSA 10-20 or Grade Group 2 (Gleason 3+4), stage T2b-T2c, less than 50 percent cores positive.
Unfavorable Intermediate Risk	Grade Group 3 (Gleason 4+3) or two or more intermediate-risk factors, or 50 percent or more cores positive.
High Risk	PSA greater than 20, Grade Group 4-5 (Gleason 8-10), or stage T3a. Germline testing is now strongly recommended.
Very High Risk	Stage T3b-T4, Grade Group 5, primary Gleason pattern 5, or more than four cores of Grade Group 4-5.
Regional (N1)	Cancer has spread to nearby pelvic lymph nodes.
Metastatic (M1)	Cancer has spread to bones, distant lymph nodes, or organs. Subdivided into mHSPC (hormone-sensitive) and mCRPC (castration-resistant).

 

Common Treatment Categories

One thing worth understanding before you compare these: surgery risk shows up fast and is fairly binary, you either have the complication or you do not. Radiation side effects are usually a slow burn that can take three to five years or more to fully show up, which is also part of why long-term studies comparing the two are harder to read cleanly than they look at first glance.

• Active surveillance: Close monitoring without immediate treatment. Standard for low-risk and select favorable intermediate-risk disease. PSA every 3-6 months, annual MRI and digital rectal exam and biopsy every 1-2 years, among other markers. This is not appropriate for Metastatic Disease.
• Radical prostatectomy: Surgical removal of the prostate. Robotic-assisted laparoscopic surgery is now the standard approach at experienced centers, but there are pros and cons to both open and robotic so please discuss with your surgeon.
• External beam radiation (EBRT): Including IMRT, SBRT, and proton therapy. Often combined with ADT for intermediate or high-risk disease. Some offices offer multiple types, others offer just one. It is worth having a consult with more than one radiation oncologist to get their full perspective. Please note: The 5-treatment SBRT schedule is convenient, but it carries a somewhat higher risk profile than the standard 20 to 28 treatment schedule. That trade-off is worth discussing directly with your radiation oncologist.
• Brachytherapy: Radioactive seeds placed inside the prostate. Can be used alone for low or favorable intermediate risk, or combined with EBRT for higher-risk disease. Seeds come in two main types: temporary (HDR) seeds that are removed after treatment, and permanent (LDR) seeds that stay in place for good. Ask your radiation oncologist which type fits your anatomy and your case.
• Androgen deprivation therapy (ADT): Lowers testosterone, which prostate cancer feeds on. Includes LHRH agonists (leuprolide), LHRH antagonists (degarelix, relugolix). Relugolix is oral, a meaningful quality-of-life option and also has less risk of cardiac function and heart health (yet not always covered by insurance). One more nuance worth knowing: the original research proving ADT improves outcomes was done before PSMA scans existed. Doctors today are re-examining exactly how much benefit ADT provides and for whom, since some men who appeared to relapse on ADT may have already had undetected spread that could not be seen at the time. This does not mean ADT is not worth using. It means the decision deserves a direct, honest conversation with your radiation oncologist about whether it is right for your specific situation.
• Androgen receptor pathway inhibitors (ARPIs): Abiraterone, enzalutamide, apalutamide, darolutamide. Now used across the disease spectrum from high-risk localized (perioperative) to metastatic.
• PARP inhibitors: Olaparib, rucaparib, niraparib, talazoparib. For HRR-mutated disease. Akeega (niraparib plus abiraterone) FDA-approved December 2025 for BRCA2-mutated mCSPC.
• 177Lu-PSMA-617 (Pluvicto): Radioisotope therapy (aka Radioligand therapy) targeting PSMA. As of March 2025 FDA expansion (PSMAfore), may now be used BEFORE chemotherapy in PSMA-positive mCRPC after one ARPI. PSMAddition data (ASCO 2026) support expansion into mHSPC.
• Next-generation radioligand therapy (on the horizon): Alpha-emitting therapies using actinium-225, terbium-161, and lead-212 are in clinical trials showing encouraging early results. Ask your oncologist about trial options.
• Chemotherapy: Docetaxel and cabazitaxel. Used in high-volume mHSPC and mCRPC.
• Sipuleucel-T (Provenge): An autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Used less often today now that newer options have moved ahead of it, but still appropriate for some men. Worth asking your oncologist where it fits, if anywhere, in your sequence.
• Radium-223 (Xofigo): A bone-targeted radiopharmaceutical for symptomatic, bone-only mCRPC with no visceral or bulky nodal spread. Should not be combined with abiraterone plus prednisone due to a higher risk of fractures and death (ERA-223 trial).
• Pembrolizumab: Immunotherapy for the small subset of MSI-H or dMMR prostate cancers.

Standard Treatment by Risk Group

Risk Group	Standard Treatment Approach
Low Risk	Active surveillance is often the preferred option. Regular PSA, mpMRI, and confirmatory biopsy within 1 to 2 years, then repeat per schedule. Treatment only if disease progresses.
Favorable Intermediate	Active surveillance for select patients, OR beam radiation, OR brachytherapy, OR radical prostatectomy.
Unfavorable Intermediate	Radiation with or without short-term ADT (4 to 6 months) OR radical prostatectomy or combination of external beam and brachytherapy
High Risk	Radiation with or without ADT (18 to 36 months) OR radical prostatectomy with or without pelvic lymph node dissection OR combination of external beam and brachytherapy. ASCO 2026 PROTEUS trial (LBA1): Perioperative apalutamide plus ADT for 6 months before and 6 months after surgery reduced metastasis risk by 20 percent. Expected to be a new FDA submission. Also consider adding an ARPI like abiraterone or darolutamide with radiation.
Very High Risk	Radiation plus 18 to 36 months ADT plus an ARPI (abiraterone, darolutamide). OR radical prostatectomy with pelvic lymph node dissection. OR combination of external beam and brachytherapy. Perioperative apalutamide plus ADT (PROTEUS) also applies here.
Metastatic Hormone-Sensitive (mHSPC) at diagnosis	ADT alone is now discouraged per NCCN v5.2026 unless there are clear contraindications. Standard: ADT plus an ARPI (abiraterone, apalutamide, enzalutamide, or darolutamide).
Metastatic Hormone-Sensitive (mHSPC) post treatment	TBD based on where disease reoccurs (prostate, bones, pelvis, etc.)
Metastatic Castration-Resistant (mCRPC)	Sequential lines of therapy: ARPI switch, docetaxel, cabazitaxel, PARP inhibitors (for HRR-mutated), 177Lu-PSMA-617 (Pluvicto) now usable BEFORE chemotherapy after one ARPI (March 2025 FDA expansion, PSMAfore trial). Alpha-emitting radioligand therapies (actinium-225, terbium-161) in clinical trials showing early promise. Sipuleucel-T for asymptomatic or minimally symptomatic mCRPC. Pembrolizumab for MSI-H disease. Radium-223 (Xofigo) is an option for symptomatic, bone-only disease without visceral spread, and is not combined with abiraterone plus prednisone due to fracture and survival risk seen in the ERA-223 trial.

 

ASCO 2026 Practice-Changing Update: The PROTEUS phase 3 trial (LBA1 Plenary, New England Journal of Medicine, May 31, 2026) demonstrated that perioperative apalutamide plus ADT for 6 months before and 6 months after radical prostatectomy reduced metastasis or death by 20 percent and made patients 9 times more likely to have little to no cancer remaining after surgery. Ask your surgeon about this if you have high risk or very high risk and are considering Prostatectomy. This is the first trial to demonstrate this benefit in high-risk localized prostate cancer and is expected to change practice. Ask your surgeon about this approach if you have high-risk or very high-risk localized disease.

 

How Hormone Therapy Actually Works

Hormone therapy shows up in almost every metastatic treatment plan, so it is worth understanding what it is actually doing inside the body.

Prostate cancer cells feed on male hormones, mainly testosterone. Hormone therapy, called androgen deprivation therapy or ADT, cuts off that fuel supply. It does this one of two ways: by stopping the testicles from making testosterone, or by blocking testosterone from attaching to the cancer cell. When the fuel drops, a large share of cancer cells die off and tumors shrink. That is why PSA usually falls quickly once treatment begins.

The Ways to Get There

• Surgery to remove the testicles: Called an orchiectomy. A one-time outpatient procedure that lowers testosterone quickly and permanently. It is by far the least expensive option and it requires no ongoing injections, pills, or prior authorizations. It is permanent, which is why many men choose medication instead, but it belongs on the menu and it is rarely offered. If simplicity and cost matter to you, ask about it.
• LHRH agonists: Leuprolide and goserelin, given as injections. These are the most commonly used option. LHRH agonists work by overwhelming a signal in the brain. To do that, they first cause testosterone to spike before it drops. This is called the flare, and it happens in the first days to weeks.

For most men it passes quietly. For a man with disease in the spine or with a urinary blockage, a testosterone surge can briefly make things worse. That is why a short course of an antiandrogen pill is given for 2 to 4 weeks when starting an agonist.

• LHRH antagonists: Degarelix by injection and relugolix by pill. These lower testosterone directly. Relugolix (Orgovyx) is taken once daily by mouth and has shown a lower risk of cardiac events, though insurance coverage varies. The antagonists do not cause a flare at all, which is one reason they are sometimes chosen when disease is bulky or already causing symptoms
• Estradiol patches: Under study as an alternative. They lower testosterone effectively and bypass the liver, with fewer hot flashes but a higher rate of breast tenderness and enlargement.

Ask your doctor: am I on an agonist or an antagonist, and do I need flare protection when I start?

What Success Looks Like on Paper

The goal of hormone therapy is to bring testosterone down to what doctors call castrate level, defined as under 50 ng/dL. Some teams aim lower. Testosterone gets checked periodically, often every 3 months while the disease is still hormone-sensitive.

This matters more than most men realize. If PSA starts rising, the very first question is whether testosterone is actually suppressed. A rising PSA with testosterone that never got to castrate level is a completely different problem than a rising PSA with testosterone fully suppressed. One means the treatment needs fixing. The other means the biology has shifted. Do not let anyone skip that check.

Ask Whether Hormone Cycling Is an Option for You

Most men are started on hormone therapy and told to stay on it. Continuous is the default, and for plenty of situations it is the right default. But there is a second approach that almost nobody hears about, and for the right man it changes daily life.

It is called intermittent hormone therapy, or hormone cycling. Instead of staying on treatment without a break, you take it until the disease is well controlled and PSA settles at a low, steady point. Then treatment pauses. Testosterone gradually comes back. Hot flashes ease, energy returns, and muscle and libido recover for many men. You stay off while PSA holds low, and you restart when PSA reaches a threshold you and your doctor agreed on ahead of time.

What the Data Actually Shows

• If your situation is a rising PSA after surgery or radiation with no visible spread: Cycling and continuous therapy have shown equivalent survival across multiple trials and pooled analyses. In this group, cycling is a widely accepted and very reasonable option.
• If you were newly diagnosed with metastatic disease: Continuous therapy is still the standard. The large SWOG 9346 trial found median survival of 5.8 years with continuous therapy compared with 5.1 years with cycling, and cycling could not be proven equally effective. Some men still choose cycling here, and that can be the right call, but it should be a fully informed choice about what you value most.
• One finding worth sitting with: In one major trial, men on cycling had more cancer-related deaths but fewer deaths from other causes, including heart disease. Less cumulative hormone therapy appears to spare the rest of the body. That trade-off is real, and it is personal.

What a Cycle Looks Like in Practice

• Treatment continues until PSA reaches a low, steady point, often after about 6 to 7 months.
• Treatment then pauses, and you are monitored with both PSA and testosterone every 3 to 4 months.
• Treatment restarts at a threshold agreed on in advance. In recurrence settings this is often somewhere between 10 and 20 ng/mL. Other protocols restart lower.
• Men on cycling are typically off treatment 35 to 50 percent of the time. The first break often lasts 6 to 15 months, and later breaks tend to get shorter.

The Honest Caveat

Testosterone does not always come back. Recovery can be slow or incomplete, especially in men over 70. That means some men take the break and never get the benefit they were hoping for.

This is exactly why testosterone has to be measured alongside PSA during every off period, not assumed. Knowing your actual number is what turns this from a hope into a strategy.

Ask your doctor: given my specific situation, am I a candidate for hormone cycling? If not right now, what would have to change for that to become an option later?

Whole-Gland vs. Partial-Gland Treatment: Know the Difference

Almost everything you just read assumes whole-gland treatment: destroying every cell inside the prostate. That is still the evidence-based, gold-standard approach, and it is where the long-term data lives. Partial-gland or focal treatment is a newer option where only the area with cancer is treated and the rest of the gland is left alone. It is not wrong, but it comes with real trade-offs you deserve to know about before you consider it.

Key questions to ask:

• “Where in the gland is the cancer and how does the location increase or reduce my risk of side effects?
• How do you do surveillance after focal therapy?
• What should PSA be after focal treatment?
• How do you treat another prostate cancer if it develops in the part of the gland not destroyed?
• How would this change the therapeutic ratio?”

Some people consider this “enhanced active surveillance”.

HIFU (high-intensity focused ultrasound): Uses focused sound waves to heat and destroy the cancerous area only.

Cryotherapy: Freezes the cancerous area instead of heating it. Sometimes used for the whole gland too.

TULSA (transurethral ultrasound ablation): MRI-guided ultrasound delivered through a catheter, done entirely from inside the body.

Electroporation: Uses targeted electrical pulses to destroy cancer cells while sparing the tissue around them.

Steam vapor therapy: Uses targeted steam to destroy tissue. More established for enlarged prostate symptoms and still emerging for cancer.

Hyperthermia: Uses targeted heat, delivered through probes or focused energy and carefully monitored in real time, to raise the temperature of just the cancerous area high enough to damage the cells while sparing tissue around it. Sometimes used on its own, and sometimes paired with radiation to make cancer cells more sensitive to it. Less established for prostate cancer than HIFU or cryotherapy, and still considered more experimental.

Focal Brachytherapy: Instead of placing radioactive seeds throughout the whole gland, seeds are placed only in and around the area with cancer, leaving the rest of the gland with a much lower dose. The goal is to get the cancer-killing power of radiation without the full-gland side effect burden. Ask your radiation oncologist whether your case and anatomy make you a candidate.

Focal Beam Radiation (Partial-Gland EBRT/SBRT): Uses precisely targeted external radiation, similar in spirit to SBRT, but shaped and focused to deliver a high dose to just the area with cancer while keeping the dose to the rest of the gland much lower. This is a newer approach and is still being studied against whole-gland radiation for long-term cancer control.

The trade-offs: focal therapy is usually not covered by insurance and can cost 15,000 to 20,000 dollars out of pocket. Your PSA will not drop to near zero the way it would with whole-gland treatment, since part of the gland is still making PSA, so the follow-up target number is different. And there is not yet a clear playbook for what to do with the untreated part of the gland if a new cancer shows up there later. None of that makes focal therapy the wrong choice. It just means you deserve to walk in with your eyes open.

The Four Scenarios Framework: Meet Every Version of Your Future Self

Nobody has a crystal ball, not you, not your doctors. Before you choose a treatment, it helps to sit with all four ways this could go. Each version of your future self deserves to be considered before you decide, not after.

• Cured, No Side Effects: The best outcome. You move on with your life and rarely think about this again.
• Cured, With Side Effects: You are healthy, but you may look back and wonder whether a different choice would have protected your quality of life just as well. This is exactly the outcome that makes informed decisions matter so much.
• Not Cured, No Side Effects: The cancer in your body was not fully controlled, but you did not experience lasting side effects. This raises a fair question worth asking your team afterward: was a more aggressive approach needed.
• Not Cured, With Side Effects: The hardest outcome. Sometimes nothing could have changed it. But you still deserve to have known every risk, and every option, before you started.

You cannot control which of these four you land on. What you can control is whether you walked in fully informed. That is the entire point of this guide.

 

PATIENT-TO-PATIENT WARNING: If you are going to need a colonoscopy in the next few years, please get one before you begin radiation. Any radiation will result in change to the anterior rectal wall which can force a biopsy that results in a fistula or other complication for no reason. Colonoscopy comes first, then radiation. Also, please ask your doctor if anal spacers would be helpful to consider to reduce your long term risk to your rectum. Please give yourself every advantage before beginning radiation!

 

Standard of care is the floor, not the ceiling. Your molecular profile, predictive molecular assays score, PSMA PET, and germline status may open doors well beyond the standard path. A Data G knows to look for those doors because we deserve personalized care.