PSA Increasing on ADT

[jfoesq]

I am 66 years old and have been on Lupron for 12 years along with Abiraterone for most of that time. PSA began rising 3 yrs ago and following a PSMA we did “wack-a-mole” on my largest tumor. PSA became immeasurable again but began rising about 6 months thereafter. PSA rising again for 2 yrs: .05, .06, .06, .09, .14, .17, .20 and .35 yesterday. What are my options and your sound recommendations if PSMA shows cancer is growing and that “wack-a-mole” is not an option? DOCETAXEL? Something else? Thank you in advance for your suggestions.

[Tall_Allen]

Consider Provenge+Docetaxel+Xofigo ±Xtandi (+Zometa or Xgeva)

prostatecancer.news/2021/02...

[jfoesq in reply to Tall_Allen]

Tall_Allen- I just read the report in the link provided. But- it is difficult for me to fully comprehend all of it. Are you suggesting I consider taking ALL of the medications you mentioned at the same time, or simply that I should consider them and decide which combination is best for me?

Thx again for your wisdom!

[Geno2853 in reply to jfoesq]

I read the report and wonder the same thing, for when I find myself in that boat. Thanks.

[NOCanceros in reply to jfoesq]

What Mr. Tall Allen means you can pick up any of those he mentioned, Tell your Dr. About the options.

[jfoesq in reply to NOCanceros]

Thx- the +signs in between each medicine threw me off

[Tall_Allen in reply to jfoesq]

A lot depends on your current status. There will never be a better time to use any or all those therapies. There are synergies:

1. Provenge may work better when the cancer kill rate is high, as it is with docetaxel and Xofigo. Also, Provenge beefs-up your immune system, which may be depleted by docetaxel.

2. Morris found he could get the same benefit from Xofigo if it was given at the same time as a lower dose of docetaxel.

3. Xtandi works longer when united with docetaxel. Xofigo+Xtandi works better than Xtandi alone in the PEACE3 trial. But,this combination MUST be given with a bone-strengthening agent (Zometa or Xgeva).

[jfoesq in reply to Tall_Allen]

Thank you VERY much!!!

[sandystarfish in reply to Tall_Allen]

Tall Allen just to understand because of cross resistance with Zytiga one should do docetaxel with Xtandi? Or then Xofigo & Xtandi? Or all 3??

[Tall_Allen in reply to sandystarfish]

You have to decide with your oncologist.

[Seasid in reply to Tall_Allen]

Your insights about combination therapies and synergies are spot-on. The timing and integration of these treatments can indeed improve their effectiveness and support the body through treatment:

1. Provenge (Sipuleucel-T): By enhancing the immune system's response, Provenge can be a strong option, especially when cancer cells are actively being targeted by treatments like Docetaxel or Xofigo. The immune support it offers may counter some of the immune suppression often caused by chemotherapy, potentially improving overall resilience.

2. Xofigo (Radium-223) with Docetaxel: Dr. Michael Morris’s findings on combining Xofigo with a reduced dose of Docetaxel are compelling, as this approach may maintain effectiveness while reducing potential side effects of higher-dose chemotherapy. This strategy can benefit those with bone-predominant disease by directly targeting bone metastases without overtaxing the body.

3. Xtandi (Enzalutamide) Combinations: Xtandi has shown durability in its effect when paired with Docetaxel, as well as with Xofigo in the PEACE3 trial. Given that bone health can be compromised during such intensive treatments, the necessity of bone-strengthening agents like Zometa or Xgeva cannot be overstated, as they help mitigate the risk of fractures and maintain structural stability in bones affected by metastasis.

These synergies could indeed maximize the cancer-kill rate while balancing side effects, but as you noted, timing is crucial. Each therapy has an optimal window, and initiating combinations at the right stage might be more effective than sequential treatment. Working closely with your oncologist to synchronize these options based on your current health and PSA dynamics will be essential in making the most of each.

ChatGPT said

[j-o-h-n]

Are you a "Morris" man?

Good Luck, Good Health and Good Humor.

j-o-h-n

[jfoesq in reply to j-o-h-n]

My MO is Dana Rathkoph at MSKCC in NYC

[j-o-h-n]

And mine is Michael Morris.... 2nd floor at Sidney Kimmel center (68th and First).

I Guess you're a Dana dame....

Good Luck, Good Health and Good Humor.

j-o-h-n

[j-o-h-n]

I just did a bit of research and it appears I've asked you the same question at least 5 times in the recent past. Please forgive me but my memory reminds me to forget what I remember.

Good Luck, Good Health and Good Humor.

j-o-h-n

[jfoesq in reply to j-o-h-n]

No problem. Wishing you the best.

[Seasid]

It sounds like you've managed quite a journey with advanced prostate cancer, and you’ve done well to keep your PSA low for so many years on ADT and Abiraterone. Your gradual PSA rise, even though slow, suggests some treatment resistance may be developing.

Since you've been on Lupron and Abiraterone for such an extended period, a few possible options could include:

1. Docetaxel or Cabazitaxel: If you're considering chemotherapy, Docetaxel is commonly used in prostate cancer, especially if PSMA imaging shows progressive disease. Some patients with prior resistance to Abiraterone or other hormonal therapies respond well to chemotherapy, which might keep things under control.

2. Switching Hormonal Therapies: If you haven't tried Enzalutamide, it could be worth discussing with your oncologist. Although similar to Abiraterone, it works differently and might provide additional suppression if resistance to Abiraterone is developing.

3. Radium-223 or Lutetium-177 (PSMA Therapy): If PSMA imaging shows uptake in certain locations, PSMA-targeted therapies like Lutetium-177 could be beneficial, although they aren’t suitable for all cases. Radium-223 can also be an option for bone metastases.

4. Local Treatments for Specific Sites: Even if "whack-a-mole" approaches (like focal radiation) become challenging, it may still help control disease in certain areas. However, this strategy depends on whether you’re seeing new isolated lesions or diffuse spread.

5. Clinical Trials: Since you've been on treatment for many years, you might want to look into clinical trials offering novel therapies, particularly if they target the resistance pathways developing against traditional hormone treatments.

Each option has its considerations, so discussing the balance of efficacy, potential side effects, and your quality of life with your oncologist could help narrow it down.

ChatGPT said

[Seasid in reply to Seasid]

Why didn't you recommend provenge? (It's me István)

[Seasid in reply to Seasid]

You're right to highlight Provenge, as it can be a valuable option for metastatic castration-resistant prostate cancer (mCRPC). Its immune-boosting mechanism is unique compared to other treatments, and it's particularly effective for patients with a low disease burden or slower PSA rise, as it primes the immune system against the cancer over time. In combination with treatments that increase the visibility of cancer cells to the immune system, such as chemotherapy or Xofigo, Provenge can be more impactful.

I didn’t mention it initially because many doctors focus first on therapies with direct PSA-lowering effects like Docetaxel or hormonal agents. Provenge's effect may not be immediately reflected in PSA levels but rather in long-term survival, making it less obvious as a first-line choice in progressive disease. However, for patients who are candidates, it’s worth serious consideration early on or as part of a multi-modal approach, especially if PSA increases have been gradual and other treatments have provided sustained control up to this point.

ChatGPT replied

[Seasid in reply to Seasid]

Q. Why MSK cancer centre didn't recommend provenge to this patient?

A. Memorial Sloan Kettering (MSK) Cancer Center and other leading institutions sometimes prioritize treatments that have a more immediate impact on tumor burden or PSA reduction, especially in cases of progressive disease after years on hormone therapy, as with this individual. Provenge is an immunotherapy that generally provides a survival benefit without directly lowering PSA or tumor volume, which can lead oncologists to opt for other therapies first when the disease is showing signs of activity or resistance.

Another factor might be that Provenge is often considered most effective in patients with a relatively low-volume disease and minimal or no symptoms. Since this man has been experiencing PSA progression over several years, MSK may have concluded that more aggressive treatments like chemotherapy or radiation would offer quicker control.

Additionally, MSK and other centers tend to base recommendations on clinical evidence and might prioritize therapies shown to have synergistic effects in trials, such as the combinations of Docetaxel with other agents. Provenge could still be considered in the future, especially if combined with other treatments like Docetaxel to enhance the immune response.

Q. Why not now? His PSA is still very low on Abiraterone plus prednisolone alone?

A. Good question—if his PSA is still relatively low on Abiraterone and Prednisolone, he might indeed be a good candidate for Provenge right now. MSK or similar centers sometimes prioritize therapies that yield a direct, measurable response in PSA or tumor shrinkage, but with his PSA still low, Provenge could potentially offer the advantage of an immune-mediated survival benefit without needing to wait for more progression.

Provenge works best when used early in metastatic castration-resistant prostate cancer (mCRPC) before the disease burden becomes high. Given that his PSA rise has been gradual, Provenge could synergize well with Abiraterone to reinforce the immune response at this stage, possibly extending the period of control before needing to shift to chemotherapy or other more intensive treatments. If he and his oncologist are open to multi-modal treatment planning, Provenge now could be a proactive step to bolster his immune defense without significantly interrupting his current regimen.

[Seasid in reply to Seasid]

We just want provenge early for the patient because that is the best for the patient. (István)

A. That makes sense, especially given that early Provenge may offer the best potential for strengthening the immune response and potentially extending control over the disease. Introducing Provenge while the cancer burden is low aligns well with its intended use, and it might support better outcomes by allowing the immune system to mount a stronger defense before the disease progresses further.

If MSK hasn’t yet offered Provenge, a conversation with the oncology team specifically about this approach could be valuable. You could ask them to outline how early Provenge fits into their treatment philosophy or whether they might consider starting it soon based on its potential benefits in this specific case.

[jfoesq in reply to Seasid]

Seasid- Thank you very much for providing me with this information. I am scheduled to see my MO on Nov. 11 and have already requested she consider ordering a PSMA and/or PET, before my appointment. FYI- when dx 12 yrs ago, I only had a few Mets (4-5), and I don’t believe any new mets developed during the last 12 yrs based upon my last PSMA about 1-2 yrs ago. One of them was in a lymph node that was removed, along with 30+ other healthy lymph nodes, when I had my prostate removed. (Yes- I know- the prostate surgery was not SOC but my MO at the time thought there was a remote possibility it might be helpful and since I was only 54 and otherwise healthy, he thought the risk of surgery was worthwhile- I was only his 13th patient to have the surgery when mets were already present). One of those tumors is in my right hip, which has been causing me some pain when I lie on my right side, so I am hopeful a PSMA shows growth to only that tumor. Other mets consist of 2 in my vertebrae and maybe 2 in my ribs. I am hopeful walk-a-mole might be recommended and be of some help to me. And, of course I will discuss all of the info provided by both Tall_Allen and you with my MO to determine the best way to proceed.

Many thx!

[Seasid in reply to jfoesq]

Q. How provenge goes together with emerging future immunotherapies?

A. Provenge (sipuleucel-T) is a type of immunotherapy known as a cancer vaccine, primarily used to treat metastatic, castration-resistant prostate cancer. It works by stimulating the patient's immune system to target prostate cancer cells. While Provenge was groundbreaking as one of the first FDA-approved cancer vaccines, it represents an earlier generation of immunotherapy compared to emerging approaches like CAR-T cells and newer antibody treatments.

Here’s how Provenge relates to emerging immunotherapies and their future roles:

1. Mechanism and Approach Differences:

Provenge: It activates the immune system by exposing immune cells to prostate cancer antigens in a lab setting, which primes the immune cells to attack prostate cancer once reintroduced into the patient.

CAR-T and Antibody-Based Therapies: CAR-T cells and other antibody treatments (like bispecific antibodies and checkpoint inhibitors) target specific markers on cancer cells more directly. CAR-T cells, for example, are engineered to recognize and kill cells with specific antigens, making them very effective for some cancers, especially blood cancers.

2. "Cold" vs. "Hot" Tumors:

Prostate cancer is often classified as a “cold” tumor, meaning it has limited immune activity within the tumor environment. Provenge has shown that it can have a modest effect on extending survival in some prostate cancer patients. However, combining it with other therapies that increase immune activity in the tumor could boost its effectiveness.

Newer immunotherapies, like CAR-T and certain antibodies, are being studied to turn these "cold" tumors into "hot" ones, thereby making them more responsive to immune-based treatments. CAR-T for solid tumors is challenging but advancing, and several research efforts aim to develop CAR-T and antibodies that can penetrate and act within the solid tumor microenvironment.

3. Potential for Combination Therapies:

Combining Provenge with other immunotherapies could enhance its effects. Provenge could be used as an initial step to prime the immune system, followed by treatments like checkpoint inhibitors or antibody therapies that help sustain and intensify the immune response.

Additionally, emerging vaccine strategies for cancer may involve using similar antigen-based or mRNA approaches, potentially with more robust immune activation mechanisms. These could serve as follow-ups or boosters to Provenge-type therapies, creating multi-step immune responses.

4. Future Outlook on Cancer Vaccination:

In 10-15 years, we may see advanced personalized cancer vaccines, CAR-T, and antibody therapies used for a range of cancers, including traditionally “cold” tumors like prostate cancer. Provenge’s role in this future landscape may be as part of a multimodal therapy approach, helping initiate or complement the immune response sparked by more aggressive therapies.

Overall, Provenge aligns with the trend toward more sophisticated immunotherapies and could benefit from combination with other modalities to improve outcomes for prostate and other cancers.

Q. I believe that if you had provenge than you can't get CAR-T? Is it possible?

A. It’s true that there can be limitations or complications when combining certain immunotherapies like Provenge and CAR-T. However, getting Provenge doesn’t necessarily exclude someone from receiving CAR-T later, though the specifics depend on the type of cancer, prior treatments, and individual patient factors. Here’s a breakdown:

1. Potential Challenges with Sequential Immunotherapy:

Immune System Exhaustion: Provenge stimulates the immune system, and CAR-T therapy also relies on a robust immune response. There’s a possibility that Provenge could contribute to T-cell exhaustion or other immune changes that might impact the effectiveness of CAR-T cells. For CAR-T to be effective, the immune system needs to remain responsive, and overstimulation from prior immunotherapy might reduce this responsiveness.

T-cell Quality: CAR-T requires high-quality T cells to be harvested from the patient. If a patient has received extensive immune therapy or if Provenge has led to significant immune changes, it may affect the ability to harvest effective T cells. However, this effect varies greatly from person to person and might not completely rule out CAR-T eligibility.

2. Clinical Trials and Safety Data:

As of now, there is limited data on the direct combination of Provenge and CAR-T for prostate cancer or other solid tumors, as CAR-T therapy for solid tumors (like prostate cancer) is still largely experimental. For patients with blood cancers, sequential or combination immunotherapies are more common, but this has not yet translated extensively to prostate cancer.

Some clinical trials are investigating combination approaches, including cancer vaccines and CAR-T. For instance, the possibility of using vaccines to prime the immune system before CAR-T is a concept under exploration. This approach, if proven safe and effective, could eventually influence how treatments like Provenge are sequenced with CAR-T.

3. Current Practice and Personalized Approaches:

In current practice, if Provenge has been administered, oncologists may carefully evaluate the immune status of the patient before proceeding with CAR-T. As CAR-T and Provenge work differently, they could theoretically be used together, but this would be done on a case-by-case basis, likely within a clinical trial setting to closely monitor outcomes and manage potential interactions.

So, while having Provenge doesn’t automatically rule out CAR-T, it does mean that careful consideration is required before introducing another immune-based therapy. As research progresses, we may see more structured guidelines on how to safely combine or sequence Provenge, CAR-T, and other immunotherapies for prostate cancer.