Figuring Out the Optimal treatment Sequence
- Androgen deprivation therapy (ADT) is the backbone of prostate cancer treatment, but when cancer becomes resistant to the treatment, known as castration-resistant prostate cancer, or CRPC, there are many additional options available to help keep the cancer under control.
- The “sequencing” — or the order in which these treatments are given — is a key part of your care plan and depends on many factors, including what treatments you’ve already received, where your cancer has spread, whether you have symptoms, and your PSA doubling time.
- For patients with non-metastatic CRPC, the approach may include adding a second-generation androgen receptor blocker.
- For patients with metastatic CRPC (meaning it has spread), there are an array of potential treatments, including androgen receptor pathway inhibitors (ARPIs), chemotherapy, radioligand therapy, and more.
Patients should know that there are many effective treatments available today to help manage this disease and help maintain your quality of life.
Read MoreWhat Is Castration-Resistant Prostate Cancer?
When you were first diagnosed with prostate cancer, it’s very likely that your initial treatment involved androgen deprivation therapy (ADT), either alone or with other medications. This therapy aims to lower the levels of male hormones, called androgens, in your body because these hormones fuel prostate cancer growth. This is why it’s often referred to as “hormone-sensitive” or “castration-sensitive” prostate cancer at that stage. ADT works by reducing your testosterone to very low, or “castrate,” levels, typically below 20 ng/dL.
However, over time, most prostate cancers find ways to grow even when these male hormone levels are very low.
Castration resistance “happens to all of the men that we treat with ADT,” Dr. Tester tells SurvivorNet. “It’s hard to predict exactly when that day is going to come, but when we see the PSA consistently rising, or the patient developing new sites of metastatic disease, you know, that’s a signal to us that they’re becoming castrate resistant.”
Diagnosing Castration-Resistant Prostate Cancer
The journey to diagnosing CRPC usually begins with signs that your disease is progressing while you are on ADT. The most common initial sign is a rising level of prostate-specific antigen (PSA) in your blood. PSA is a protein produced by prostate cells, and an increase can indicate that the cancer is becoming more active.
Beyond PSA, your doctor will likely recommend imaging tests to see if the cancer has spread or grown.
Conventional imaging traditionally includes scintigraphy (bone scan) to check for spread to the bones, and a CT scan of the chest, abdomen, and pelvis (or an MRI if CT is not suitable) to look for disease in other organs.
However, there are newer, more sensitive imaging techniques, such as PET scans (positron emission tomography) using prostate-specific radionuclides (PSMA PET/CT). Several oncologist explained to SurvivorNet that PSMA PET scans are preferred over bone scans because of their improved sensitivity to detect sites of disease.
These newer scans are much better than conventional imaging at finding small areas of cancer that might otherwise be missed. For instance, studies have shown that PSMA PET/CT can identify cancer lesions in nearly all men with non-metastatic CRPC and a short PSA doubling time, even finding metastatic disease in over half of these men where conventional imaging was negative.
When CRPC is diagnosed, your doctor will determine the extent of your disease:
- Non-metastatic CRPC means your PSA is rising, but imaging (CT, MRI, or PET) does not show any new cancer spread outside the prostate to other sites, like lymph nodes, organs, or bones.
- Metastatic CRPC means the cancer has spread beyond the prostate to other parts of your body, such as bones or other organs.
What Influences My Prognosis?
Understanding your prognosis, or the likely course of your disease, is a natural concern. CRPC is not a single disease, but rather a group of different situations, and your individual prognosis depends on several factors.
“I don’t think the genomics are very important at the beginning, and they’re not very predictive either, aside from the few cases of neuroendocrine cancer that we have. But for most men, it has more to do with the extent of disease, the number of bone metastases, the presence or absence of visceral metastasis and other factors related to their medical comorbidity, such as cardiovascular health, previous stroke or previous myocardial infarctions” Dr. Tester says.
Key factors that help with prognosis include:
- Site and extent of metastatic involvement (spread)
- PSA doubling time (how quickly PSA is rising is an important prognostic factor for patients with non-metastatic CRPC)
- Other clinical parameters (such as pain requiring opioids, elevated levels of certain enzymes in your blood like LDH and ALP, lower albumin and hemoglobin levels)
Doctors can combine these factors into tools called “nomograms” to help estimate your risk.
The Role Of Genetic Testing
A significant advancement in prostate cancer care is the recognition that genetic factors play a crucial role. For all men with metastatic prostate cancer, including CRPC, germline genetic testing and next-generation sequencing of tumor tissue are strongly suggested.
Germline genetic testing looks for inherited mutations in your genes (like BRCA1, BRCA2, ATM, PALB2, CHEK2, and genes for Lynch syndrome) that you were born with. These mutations can affect how your cancer behaves and, critically, can influence which therapies might work best for you, such as PARP inhibitors. This testing also has implications for your family members.
Next-generation sequencing of tumor tissue (somatic testing) looks for mutations that developed in your cancer cells over time. These findings can reveal specific vulnerabilities in your cancer that can be targeted with approved drugs (like PARP inhibitors for homologous recombination repair deficiency, or pembrolizumab for specific mismatch repair deficiencies) or may make you eligible for clinical trials. These tests are becoming increasingly vital as they help tailor treatments to your cancer’s unique genetic fingerprint.
Navigating Treatment Options For CRPC
The good news is that there are many active treatment options for CRPC. The “sequencing” — or the order in which these treatments are given — is a key part of your care plan and depends on many factors, including what treatments you’ve already received, where your cancer has spread, whether you have symptoms, and your PSA doubling time. Working closely with your doctor to decide on the best path for you is essential.
For most men with CRPC, it is recommended to continue your androgen deprivation therapy (ADT) while adding other systemic treatments.
“The backbone of treatment is androgen deprivation,” Dr. Tester explains. “Androgen receptor analogs like abiraterone (brand name Zytiga), apalutamide, enzalutamide and darolutamide don’t lower testosterone levels the way that ADT does. In fact, they don’t lower it at all. If you don’t give ADT and you give a drug like enzalutamide, the testosterone level generally goes up.”
Even though the cancer is “castration-resistant,” continuing to keep testosterone levels low is important because male hormones are still growth factors for prostate cancer, and stopping ADT could cause the disease to progress more rapidly.
If your initial hormone therapy included an older antiandrogen medication (like flutamide, nilutamide, or bicalutamide) along with a GnRH agonist, your doctor will likely suggest withdrawing the antiandrogen before starting a new treatment. Sometimes, simply stopping this older medication can lead to a temporary improvement in your PSA or symptoms.
Treatment For Non-Metastatic CRPC
If you have CRPC, but scans don’t show any spread (meaning you have non-metastatic CRPC, or nmCRPC), the primary concern is often a rising PSA.
For men with non-metastatic CRPC whose PSA is doubling in 10 months or less, there are specific treatments that have been shown to delay the spread of cancer and prolong survival.
Oncologists usually suggest adding a second-generation androgen receptor blocker like enzalutamide, apalutamide, or darolutamide to your continued ADT. These medications work by further interfering with the androgen receptor signaling pathway within the cancer cells, even at very low testosterone levels. All three are approved by the US Food and Drug Administration (FDA) for this specific situation.
While they work similarly, their side effect profiles can differ. For instance, darolutamide may cause fewer central nervous system side effects than enzalutamide or apalutamide because it doesn’t cross into the brain as much. Your doctor will help you choose based on your individual health and potential side effects.
For longer PSA doubling times, the optimal approach is less clear. Observation alone is a reasonable option, or your doctor might consider an ARPI if it hasn’t been used before.
Treatment For Metastatic CRPC
If your CRPC has spread to other parts of your body, you have metastatic CRPC (mCRPC). The treatment choices here are heavily influenced by what therapies you’ve already received, as advances in treating earlier stages of prostate cancer mean many patients now receive treatments like docetaxel or ARPIs before CRPC develops.
ARPIs
For patients who have not had an ARPI or a Taxane yet, adding an androgen receptor pathway inhibitor (ARPI) to your ADT is the preferred initial approach.
- Abiraterone blocks the production of androgens in the testes, adrenal glands, and even within the tumor cells themselves. It’s typically taken with prednisone to manage potential side effects like high blood pressure or low potassium.
- Enzalutamide blocks the androgen receptor directly, preventing male hormones from signaling cancer growth. It works at multiple points in the pathway. Unlike abiraterone, it doesn’t usually require concurrent steroids.
Choosing between abiraterone and enzalutamide often comes down to their different side effect profiles, your other medical conditions, and sometimes insurance coverage. For example, abiraterone might cause less fatigue but has a higher risk of affecting blood sugar, while enzalutamide has a very low risk of seizures and can interact with blood thinners.
Chemotherapy
While ARPIs are often preferred, docetaxel chemotherapy may be considered early on for patients with rapidly progressing or very symptomatic disease, especially if ARPIs might not be fast enough. Docetaxel plus prednisone has been a standard chemotherapy regimen for CRPC.
“There’s two real major standard chemotherapies for prostate cancer. One’s called docetaxel, and another one is a sister drug called cabazitaxel, very similar drugs,” Dr. W. Kevin Kelly, Chair of the Department of Medical Oncology at Thomas Jefferson University in Philadelphia, tells SurvivorNet.
“They’re given through the veins, typically every three weeks. In general, they’re well tolerated. If you think that that the worst chemotherapy we give is a 10. This is around a two or three, so it’s on the mild side of the chemotherapy. Major toxicities can be you can have some hair loss, nausea or vomiting,” he adds.
Immunotherapy
A unique type of immune therapy — sipuleucel-T is a cellular vaccine for men with minimally symptomatic, slowly progressive disease. It helps your own immune system recognize and fight the cancer. It does not significantly affect PSA or tumor size, so its impact on an individual can be hard to measure, but it has been shown to prolong survival in appropriate patients.
Bone-Targeted Therapy (Radium-223)
If your cancer has spread only to the bones and is causing symptoms, but you don’t have visceral (organ) metastases, Radium-223 is an option. It’s a radioactive agent that targets bone metastases to deliver localized radiation, helping to relieve pain and improve survival.
Other Sequencing Options
If your cancer has progressed despite ARPIs, your doctor will often recommend taxane-based chemotherapy like docetaxel or cabazitaxel.
Many clinicians still choose docetaxel as the initial chemotherapy. However, cabazitaxel is also an option and may be preferred for older or frail patients, or those at high risk for low white blood cell counts, due to its potentially lower toxicity and similar effectiveness. While cabazitaxel is FDA-approved for patients after docetaxel, studies have shown it can be comparable to docetaxel in chemotherapy-naïve patients, with different side effect profiles (e.g., less neuropathy and hair loss with cabazitaxel, but more hematuria).
Radium-223 also remains an option for these patients if they have symptomatic bone metastases without visceral spread.
If your genetic testing (germline or somatic) reveals specific mutations, such as homologous recombination repair (HRR) deficiency (e.g., BRCA2 mutation), you may be eligible for PARP inhibitors. These medications target the cancer’s inability to repair its DNA, leading to cancer cell death.
Targeted Therapy: Pluvicto
Lutetium Lu-177 vipivotide tetraxetan (PSMA-targeted radioligand therapy – brand name Pluvicto) is a newer, FDA-approved option for patients whose cancer is PSMA-positive (meaning it expresses a protein called PSMA, which can be seen on a specific type of PET scan).
As of March 28, 2025, the FDA expanded the use of Pluvicto for adults with PSMA-positive mCRPC who have been treated with an androgen receptor pathway inhibitor (ARPI) and are eligible to delay chemotherapy.
This is a major step forward.
Until now, Pluvicto was only available for patients who had already undergone chemotherapy. Now, it can be used earlier, before chemo is required, tripling the number of eligible patients and giving many more men the chance to access this innovative therapy.
Studies have shown it improves overall survival and time to progression compared to standard care in this setting, often with a more favorable side effects profile than chemotherapy.
Pembrolizumab
This is an immune checkpoint inhibitor that may be an option if your tumor shows specific features like deficient mismatch repair (dMMR) or high levels of microsatellite instability (MSI-H).
This therapy works by “unleashing” your immune system to attack cancer cells.
The FDA has approved pembrolizumab for certain advanced solid tumors with these characteristics, including prostate cancer, when other treatments haven’t worked or aren’t tolerated.
Investigational Treatments & Clinical Trials
It is important to emphasize that participation in clinical trials should be considered whenever possible. These trials offer access to the newest therapies and approaches, and they are crucial for advancing our understanding and treatment of prostate cancer.
Your doctor can discuss if there’s a clinical trial that might be a good fit for you. For example, bipolar androgen therapy (BAT), which involves rapid cycling between high and low testosterone levels, is an investigational approach aiming to resensitize CRPC to hormone therapies. While early studies are promising, more research is needed to determine its optimal use. Another investigational approach for oligometastatic disease is combining stereotactic body radiation therapy (SBRT) with abiraterone.
Questions To Ask Your Doctor
- What are my options now that my cancer has become castration-resistant?
- How will these treatments be sequenced?
- What side effects can I expect from my treatment plan?
- Are there any clinical trials I should consider enrolling in?
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