When Treatment Stops Working: Managing Metastatic Castration-Resistant Prostate Cancer

When we talk about treatment “stopping working,” we’re referring to disease progression.

“Once a patient has more advanced prostate cancer, we usually do what we call hormonal ablation, or lowering the male hormone testosterone [with treatment]. That typically lasts anywhere from three to five years. Then patients’ [cancer] cells get smarter, and they progress,” Dr. W Kevin Kelly, Chair of the Department of Medical Oncology at Thomas Jefferson University in Philadelphia, tells SurvivorNet. “At that point they’re called castrate resistant prostate cancer.”

Metastatic castrate-resistant prostate cancer, or mCRPC, is defined by a combination of factors, including:

• Low testosterone levels (below 50 ng/mL or 1.7 nmol/L). This confirms that the cancer is truly “castration-resistant,” meaning it’s growing despite low testosterone.
• New or worsening metastatic disease, typically seen on imaging scans that show cancer has either spread to new areas or existing metastatic sites have grown.
• Rising PSA levels

It’s very important to know that a rising PSA alone is generally not enough to declare progression unless there’s also clinical or radiographic evidence of the disease advancing.

To assess your situation, your doctors will rely on a combination of evaluations including clinical assessments (discussing your symptoms and overall health), blood tests to monitor PSA and other markers like alkaline phosphatase (AP), which can indicate bone involvement,  and radiologic assessments like Tc99 bone scans and CT scans of your chest, abdomen, and pelvis (CT CAP). These scans are often done every 3-6 months, or sooner if there’s a significant rise in PSA or new clinical symptoms suggesting progression.

You might also hear about PSMA PET-CT scans. While these are very helpful for identifying PSMA-expressing tumors (especially if a specific treatment called 177Lu-PSMA-617 is being considered) or for staging when conventional scans don’t show clear progression, they are not routinely used to assess how well treatment is working because the research on their use for this purpose is still emerging.

Navigating Your Next Treatment Steps

When a treatment stops working, it signals that your cancer has found a way to adapt. But just as your cancer adapts, so do the treatment strategies available.

The standard of care for castration-resistant prostate cancer depends on what prior therapies a patient has had, Dr. Kelly says.

Your specific cancer characteristics (especially genetic changes), your overall health, and your personal preferences will also be key in determining the path forward.

Regardless of other treatments, you will continue androgen-deprivation therapy (ADT) indefinitely to keep testosterone levels low. ADT is the backbone of prostate cancer therapy, because the cancer feeds off male hormones. Even when ADT stops working as well, it still plays a role.

Androgen receptor pathway inhibitors (ARPIs) can be added to the treatment plan to help control the progression.

The American Society of Clinical Oncology also strongly recommends both germline and somatic genetic testing for patients with metastatic prostate cancer as early as possible. These tests look for inherited and acquired gene changes in your cancer cells, like BRCA1/2 or other homologous recombination repair (HRR) gene alterations. These changes can unlock highly effective targeted therapies.

If your cancer has spread to your bones, your doctor will likely recommend bone-protective agents, such as denosumab or zoledronic acid. These medications help strengthen your bones and reduce the risk of serious skeletal-related events, like fractures or spinal cord compression.

After ADT, The Next Steps

If your mCRPC has progressed after initially being treated with ADT alone, your doctor will consider several options, which might include targeted therapy, ARPIs, chemotherapy, and more.

Here’s a break down of the options.

Targeted Therapy

If you have BRCA1/2 alterations, a combination of a PARP inhibitor (like niraparib, olaparib, or talazoparib) and an androgen receptor pathway inhibitor (ARPI), like abiraterone with prednisone or enzalutamide, is often the preferred choice. This combination has shown significant benefits in slowing cancer progression and improving overall survival.

If you have other HRR gene alterations (such as PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12), the combination of talazoparib and enzalutamide may be suggested, especially since we’ve seen benefits in slowing progression, particularly in those with PALB2 and CDK12 changes.

Standard Single-Agent Therapies

• Androgen Receptor Pathway Inhibitors (ARPIs): Options include abiraterone with prednisone or enzalutamide. These medications work by further blocking the male hormones that fuel prostate cancer growth.
• Chemotherapy with docetaxel: This is another effective option. Docetaxel has been shown to improve overall survival.

“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. Kelly explains.

“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.

While there’s limited data, other ARPIs like darolutamide or apalutamide can be used if there are concerns about side effects or drug interactions with abiraterone or enzalutamide. If you experience side effects like feet/fingers numbling (neuropathy) from docetaxel, cabazitaxel is a suitable alternative chemotherapy,

The choice between an ARPI and chemotherapy often depends on your overall health, ability to tolerate chemotherapy, presence of symptoms, cost, and your personal preferences.

Situations Warranting Different Approaches

There are certain situations where the above treatments may not be used in favor of a different approach.

These include:

• Symptomatic Bone-Only Disease: If your cancer has spread primarily to your bones and is causing symptoms, radium 223 may be recommended. This radiopharmaceutical delivers targeted radiation to bone metastases, improving survival. However, it’s generally avoided in combination with abiraterone and prednisone due to an increased risk of fractures and mortality.
• Microsatellite Instability-High (MSI-H) or Mismatch Repair-Deficient (dMMR) Cancer: For these rare but specific genetic changes, pembrolizumab (an immunotherapy) has shown clinical efficacy.
• Indolent Disease Course: If your disease is progressing slowly, characterized by a slow rise in PSA, minimal or no symptoms, and low disease volume without spread to internal organs (viscera), sipuleucel-T may be suggested. It’s important to understand that sipuleucel-T doesn’t typically show objective changes on PSA levels or scans, but it has been shown to improve overall survival in selected patients.
• Oligometastatic Progression: If you have only a few new or growing metastatic sites (oligometastatic disease), your doctor might discuss metastasis-directed therapy, such as radiation or surgical removal, after a multidisciplinary team evaluation. This approach can sometimes allow you to continue on your current systemic therapy longer.

If You’ve Had Hormone Therapy & ARPI

When mCRPC progresses after treatment with an ARPI in addition to ADT, the approach shifts to other effective strategies.

Some options include:

• Targeted therapy for HRR alternations: For BRCA1/2 alterations, olaparib monotherapy is strongly recommended and has demonstrated significant improvements in both progression-free survival (PFS) and overall survival (OS). Rucaparib may also be considered as an alternative. For other HRR alternations, olaparib monotherapy may be suggested, particularly for patients with PALB2 or CDK12 changes, as they tend to experience the most benefit.
• Chemotherapy or radium 223 (if there are no HRR alternations): Docetaxel chemotherapy is a primary option. Radium 223 is an option if you have symptomatic bone-only disease, as discussed previously. Again, cabazitaxel can be considered if docetaxel is not suitable due to toxicity or allergic reactions.
• Sipuleucel-T or local therapies: These may still be options for selected patients with indolent disease or oligometastatic progression, similar to the recommendations for patients treated with ADT alone.

Options After Extensive Treatment

There are still options for cancer that has continued to progress after several attempts at treatment. One of those is a type of targeted radiation known as Lutetium-177-PSMA-617 (177Lu-PSMA-617).

If your cancer is PSMA-positive on imaging, this radiopharmaceutical therapy is a highly recommended. It has shown significant benefits in improving both progression-free survival and overall survival. If your disease is PSMA-negative, cabazitaxel or radium 223 (for bone-predominant disease) would be considered.

Chemotherapy with cabazitaxel is also a strong option in this setting and has shown superiority over switching to another ARPI. For some patients, targeted therapies or radium 223 may still be options as well.

If your disease continues to progress despite these options, your team will discuss participation in clinical trials, a combination of cabazitaxel and carboplatin (which has shown some benefit in heavily pretreated patients), or carboplatin monotherapy. Ultimately, the focus may shift towards best supportive care and hospice care to ensure comfort and quality of life.

Questions To Ask Your Doctor

• Do I need genetic testing?
• Is there a reason you recommend one treatment over another?
• What side effects should I prepare for?
• How often will I be monitored for progression?

Content independently created by SurvivorNet with support from Novartis Pharmaceuticals Corp.

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