Rethinking metastatic prostate cancer

Just three to four decades ago, men with metastatic prostate cancer lived an average of 28 to 36 months. Today, the average life expectancy of someone with this diagnosis has increased to about five to six years, and experts are starting to view metastatic prostate cancer as potentially curable — a concept that would have been unimaginable a decade ago.

Certainly, part of the shift comes thanks to improved treatments. But advances in imaging — particularly a type called PSMA-PET testing — have also been crucial.

Previously, oncologists could only diagnose metastatic prostate cancer when cancerous cells that had spread far from the prostate formed tumors large enough to be visible on CTs, MRIs, bone scans, and other conventional imaging. Given the size and progression of such metastases, eliminating these cancerous deposits was challenging. Newer PSMA-PET scans, which are now more widespread in clinical practice, have been a game-changer. Using this advanced imaging technique, doctors can detect smaller, newly formed metastases that are much more apt to be treatable or even curable with surgery or radiation.

PSMA-PET technology relies on injectable compounds called tracers that bind to a surface protein on prostate cancer cells called prostate-specific membrane antigen, or PSMA. PSMA also exists in normal prostate tissue, but is present at much higher levels in tumors. The tracers light up on a PET scan, revealing where metastatic cells are located.

As imaging has improved, patients who already know they have prostate cancer sometimes end up getting recategorized. After getting an advanced imaging test, a person who was initially diagnosed with localized cancer might learn that he has oligometastatic disease — an intermediate state between localized cancer and significant metastatic disease. Someone else who was previously diagnosed with oligometastatic cancer might find out that he has widely metastatic castrate-resistant disease (mCRPC), which is the most advanced form of prostate cancer.

How to best treat patients with small, newly diagnosed, or identified metastases, or those who have been recently recategorized thanks to advanced imaging, isn't clear-cut, and evidence supporting various approaches is still emerging. In the interim, doctors must figure out how to use different combinations of surgery, radiation, and systemic therapies to best treat each patient.

To shine a light on the complexities involved, I invited colleagues from Beth Israel Deaconess Medical Center and the Massachusetts General Hospital (both teaching hospitals of Harvard Medical School) to participate in a roundtable discussion.*

Roundtable participants:

Nima Aghdam, M.D., is a radiation oncologist at Beth Israel Deaconess Medical Center, Boston, and an instructor in radiation oncology at Harvard Medical School.

David Einstein, M.D., is an assistant professor of medicine at Harvard Medical School and a medical oncologist at Beth Israel Deaconess Medical Center.

Xin Gao, M.D., is an assistant professor of medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital.

Boris Gershman, M.D., is a urologist at Beth Israel Deaconess Medical Center and an assistant professor at Harvard Medical School focusing on prostate and bladder cancer.

Marc B. Garnick, M.D., editor in chief of the Harvard Medical School Guide to Prostate Diseases, moderated the discussion. Dr. Garnick is also the Gorman Brothers Professor of Medicine at Harvard Medical School and a medical oncologist at Beth Israel Deaconess Medical Center.

Dr. Garnick: We talk about advanced prostate cancer as falling along a spectrum. Can you explain the range to our readers?

Dr. Einstein: Advanced cancer includes metastatic cancer as well as what we call high-risk nonmetastatic cancer. High-risk nonmetastatic prostate cancer is "localized," meaning that it's still confined to the prostate gland, but it has aggressive features that predict future metastatic spread or the growth of existing metastases that are currently too small for us to detect. We would put someone with a Gleason score of between 8 and 10, or who has cancer extending beyond the prostate or PSA levels higher than 20 nanograms per milliliter (ng/mL), in this category. High-risk localized disease is potentially curable with surgery or radiation, yet there's a chance that some cancer cells have already broken free of the tumor.

Oligometastatic disease is the next step in the continuum. We generally define it as no more than three to five metastatic sites on diagnostic imaging. There could be other small cancer deposits that we still can't see with current scanning methods, but we would typically try to eradicate the visible sites.

After oligometastatic comes metastatic castration-sensitive prostate cancer, or mCSPC. It refers to metastatic disease that still hasn't been treated, or that is still responding to our first-line therapies, which are drugs that produce medical castration. Called hormonal therapies or androgen-deprivation therapy (ADT), these drugs suppress the production of testosterone, a sex hormone that drives prostate tumors to grow.

Finally, metastatic castration-resistant prostate cancer, or mCRPC, refers to widespread prostate cancer that is not responding to hormonal treatments.

Dr. Garnick: Dr. Aghdam, how do you use radiation to treat patients with either oligometastatic prostate cancer or mCSPC?

Dr. Aghdam: Certainly, patients with oligometastatic prostate cancer benefit from radiation to the metastases themselves — clinical trials have shown this. We call this metastasis-directed therapy. But there's controversy over whether localized radiation treatment to the prostate is beneficial for men with metastatic cancer. I offer it routinely to patients with isolated metastases. Localized radiation can often delay the need for additional systemic therapy with ADT and possibly chemotherapy down the line.

Dr. Garnick: What if the patient has lower urinary tract symptoms, such as obstructed urine flow, urgency, or painful urination? Can radiation to the prostate worsen these symptoms?

Dr. Aghdam: Radiation oncologists have to be careful not to jump the gun. If the cancer is causing urinary symptoms, then there's a strong case for initiating systemic therapy before you start radiation. A few months of ADT goes a long way toward shrinking the prostate tumor and addressing any associated urinary symptoms. But if the urinary symptoms predate the cancer and have other causes, then radiation can worsen the symptoms — even though it helps to control the cancer over the long term.

Dr. Garnick: Dr. Gershman, how do you decide whether a man with oligometastatic prostate cancer or mCSPC is a good candidate for surgery

Dr. Gershman: It depends on how far the cancer has spread. If the cancer hasn't spread beyond the pelvis, then surgery is a reasonable option for appropriately selected patients, especially if the tumor is obstructing urinary flow. We would advise surgery as part of a multimodal strategy that also includes systemic hormonal treatments.

I'd be hard-pressed to operate on someone with metastatic disease in the bones or any distant lymph nodes outside the pelvis. We still don't have good clinical trial data to show that a radical prostatectomy — surgery to remove the prostate — will benefit such a patient, though we may have better evidence in the future.

Dr. Garnick: What if the cancer recurs after initial treatment, but only in the lymph nodes? Would you remove the nodes?

Dr. Gershman: Probably. Studies suggest that treating recurring cancer in the lymph nodes with surgery or even radiation prolongs disease-free survival and delays the need for systemic therapy later with ADT. But the cancer does tend to progress in most patients within five years, even if you remove the lymph nodes.

Dr. Garnick: Can you explain to readers what the potential downside of removing lymph nodes might be?

Dr. Gershman: Lymph node removal is generally safe when performed at academic centers that do a lot of these procedures, but complications can occur. The likeliest complication is a lymphocele, which is a collection of lymphatic fluid, usually in the space from which a lymph node was removed. Lymphoceles occur in about 10% to 20% of lymph node dissections [which remove more nodes from a wider area compared to limited removal] performed during a radical prostatectomy. They're usually asymptomatic and resolve on their own. But in some cases, they have to be surgically drained.

There's also a small risk of lymphedema, which is an accumulation of lymphatic fluid that causes swelling in the extremities, typically the legs. The lymphedema risk is a bit higher in patients who were initially treated with radiation instead of surgery. That's because radiation can damage the channels that drain lymphatic fluids.

Dr. Garnick: How would you use ADT in a patient with lymph-node-only recurrence

Dr. Gershman: We don't have good evidence on how long we should use ADT in patients with lymph-node-only recurrence after primary localized treatment with surgery or radiation. Some evidence suggests six months is enough, but comparative evidence in favor of either short or longer-term ADT in such cases is lacking. On the other hand, if positive lymph nodes are detected during a radical prostatectomy, then there's a lot of support in favor of giving hormone therapy for two years.

Dr. Garnick: Let's discuss a hypothetical newly diagnosed patient: He's 67 years old and has a PSA level of 110 ng/mL. A prostate and pelvic MRI shows prostate cancer spreading into the seminal vesicles [glands that produce semen] and a few metastases in the bones. He also has a maternal history of breast cancer. What is the appropriate work-up for this patient?

Dr. Einstein: I'd start with a CT scan or MRI of the entire torso plus a bone scan to check for evidence of more widespread cancer. I would also recommend PSMA-PET to determine if he's eligible for curative-intent local therapy [meaning treatment with the goal of eradicating the cancer] with surgery or radiation. If we detect just a few metastases with a PSMA-PET scan, then we can treat those deposits directly [with metastatic-directed radiation or surgery] in combination with local and systemic therapy and potentially cure the disease.

Dr. Gershman: I agree with ordering a PSMA-PET scan, both on the basis of bone lesions on the MRI as well as the high PSA. A PSA over 50 or 100 generally indicates at least micro-metastatic disease [tiny clusters of cancer cells that have spread], so surgery alone is unlikely to be curative. I might still suggest surgery if the patient has obstructive urinary flow symptoms that aren't being adequately managed with hormonal therapy.

If we do opt for surgery, then I would advise combining it with additional treatments that also include ADT, either by itself or with an AR inhibitor. [AR inhibitors, or androgen-receptor inhibitors, prevent testosterone from attaching to receptors on cancer cells. The combination of hormonal systemic therapy and another drug such as an AR inhibitor is known as "doublet therapy."]

Dr. Garnick: Would you consider adding chemotherapy as well? [This would be called "triplet therapy," since it combines hormonal therapy, targeted therapy with an AR inhibitor, and chemotherapy.]

Dr. Einstein: The benefits of adding chemotherapy in such cases are still unclear. But if a patient has confirmed metastatic prostate cancer, then I think we should at least consider it, especially if he has high-volume disease, which is defined as four or more bone metastases with at least one additional metastasis located outside of the spine or pelvis.

Dr. Garnick: Could you start with doublet therapy and then add chemotherapy later if the disease progresses?

Dr. Einstein: We don't have good clinical trial data to guide that decision. But I think there is a role for adding chemotherapy for patients with newly diagnosed high-volume disease.

Dr. Garnick: If the patient wants another opinion, what would you tell him, Dr. Gao?

Dr. Gao: I agree with Dr. Einstein. If a patient with high-volume disease is otherwise healthy and willing to tolerate the additional side effects, then I favor adding chemotherapy, and there's some evidence to support that strategy. Some patients are willing to tolerate the uncertainty and side effects that come with adding chemotherapy. Others say that without more supporting evidence, they'll delay the chemotherapy for as long as possible. There's no definitively right or wrong approach in this situation.

Dr. Garnick: Which AR inhibitors are available for treating men with mCSPC?

Dr. Gao: We have several options, including abiraterone, enzalutamide, apalutamide, and darolutamide. Abiraterone (used in combination with low-dose prednisone) and darolutamide are well tolerated in my experience, and they have been best studied in combination with chemotherapy as part of triplet therapy. The various AR inhibitors have slightly different side effect profiles, and if the patient has other medical issues such as significant heart disease, diabetes, or seizure disorder, or a history of falls or gait instability, I may favor one AR inhibitor over another. Sometimes insurance coverage or other financial barriers make one AR inhibitor more or less feasible than the others. Notably, none of these drugs have been compared head-to-head in mCSPC patients, and, in general, their efficacy appears to be similar.

Dr. Garnick: Let's discuss another hypothetical patient: This individual is 76 years old, and he presents with bone pain and some difficulty in urination, but he's otherwise asymptomatic. His PSA is 4,268 ng/mL, and imaging reveals widespread metastases in the bones and lymph nodes. What would you do?

Dr. Gao: Well, there is no doubt that this is prostate cancer. You could get a biopsy to confirm, but it's not absolutely necessary unless the patient is considering joining a clinical trial [which typically requires a biopsy-confirmed diagnosis]. If he's otherwise healthy and can tolerate chemotherapy, I would lean toward an aggressive strategy with triplet-therapy.

Dr. Garnick: Should this patient also have radiation?

Dr. Aghdam: Probably. When a patient presents with pain and widespread metastatic disease, I'm always wary of fractures, particularly if the cancer is spreading into the spine or weight-bearing long bones in the legs. Radiation could shrink the tumor and make it less apt to cause a fracture or compress the spinal cord. Recent studies suggest there could even be survival advantages from this intervention.

Dr. Garnick: Prostate cancer itself, as well as the hormonal medications often used to treat it, can take a toll on bone density and lead to fractures. Should this patient have a bone density test and/or take bone-strengthening medication, such as bisphosphonates?

Dr. Einstein: This is a complex topic. Some clinical trials show no benefit from early use of bisphosphonates to prevent cancer-related fractures. It could be that hormonal therapy is so good at controlling prostate cancer during the early phase of the disease that bisphosphonates aren't necessary. I tend to order bone density scans for older patients who may be starting on long-term hormonal therapy, especially if they have additional risk factors for osteoporosis. For patients with more advanced cancer — those with mCRPC, for whom hormonal therapies are no longer working — there's absolutely a role for drugs that can increase bone density, such as bisphosphonates or RANK ligand inhibitors.

Dr. Gao: I agree that clinical trial evidence so far doesn't really support the use of bone-targeted therapy to address skeletal metastases in patients with hormone-sensitive disease. These tumors are by definition hormone-sensitive, so they are going to respond to hormonal agents, and the added benefit of a bone-targeting drug is probably pretty minimal. I also order bone density scans for patients who need long-term hormonal therapy — which usually means two years — and similarly offer a bisphosphonate to those at high fracture risk.

Dr. Garnick: In early 2024, Francis Collins, former director of the National Institutes of Health, revealed that he was diagnosed with advanced prostate cancer after being on active surveillance for five years. This news has likely alarmed many men who have chosen active surveillance for themselves. What would you want them to know?

Dr. Gershman: With routine PSAs every six months, MRI testing, and biopsies, it's really rare to have sudden progression that leads to a missed window of curative opportunity. I wonder if something was missed on biopsy during his initial work-up. We have a lot of long-term data on active surveillance, and the risk of metastatic progression for someone with a low-risk diagnosis is only 2% to 3% [within a 10- to 15-year follow up period].

Dr. Einstein: All the available data point to active surveillance as being a safe approach [for men with localized prostate cancer that is unlikely to quickly spread based on specific criteria]. With careful surveillance, you're monitoring not just the existing cancer, but also checking for newly emerging tumors in the prostate that might be more aggressive. Collins' experience shouldn't necessarily dissuade people from choosing active surveillance, provided their doctors haven't found any evidence of high-risk disease when doing a thorough baseline assessment.

Dr. Garnick: Would anyone like to share some concluding remarks

Dr. Aghdam: Thank you, Dr. Garnick, for another great discussion. It's a pleasure and honor to work with you and attend this annual roundtable. [Find the previous version in the Harvard Medical School Guide to Prostate Diseases.] I'm optimistic that we're at the edge of advancing our field to the point where we could potentially begin talking about living with advanced metastatic prostate cancer as a chronic disease. Perhaps we'll even have the good fortune of seeing these patients cured in our professional lives, and I sincerely hope that's the case. I see local therapy as part of that equation, but ultimately systemic therapy will form the backbone of future cures.

Dr. Gao: For metastatic disease, we need to use standard therapies in more optimal ways. Clinical trials are showing show real benefits from early adoption of drugs and intensified drug combinations that we traditionally reserve for patients with late-stage disease. The ability to detect small amounts of oligometastatic disease with PSMA-PET imaging means we offer more aggressive treatment to patients who might have been considered nonmetastatic with conventional imaging. But we need more research to optimize our strategies.

Dr. Gershman: In my mind, multimodal and multiagent therapy is really what's going to give you better outcomes for the most advanced or aggressive disease. The combinations and optimal timing of sequential treatments will continue to evolve, and newer agents will add to the therapeutic armamentarium.

Dr. Einstein: Clinical trials still need to show that earlier treatments will help in the long term. We don't want to increase toxicity early on if saving some tools for later would have been just as good. And does every patient need intensified therapy? Could there be a role for treatment regimens that spare men the long-term side effects of ADT? We're trying to turn metastatic prostate cancer into a chronic condition that people manage like blood pressure and diabetes. The goal is to maximize quality of life, as well its duration.

*Editor's note: Conversation has been edited for clarity.