I have mHSPC and the last PSA was <0.05 (“Undetectable”) for the first time in my journey.
I am on Eligard, Abiraterone, Prednisone, and Xgeva.
I found an MO who ordered Next Generation Sequencing from Caris based on the original prostate biopsy dated October 2023.
The results show MMR deficiency, MSI-High and TMB High with 34 mutations/Mb.
Accordingly, the MO wants me to start Keytruda immediately. He also wants to stop Eligard, Abiraterone, and Prednisone at the same time.
Another MO said it might be best to complete at least 18 months of hormone therapy. I have completed 12 months so far.
My local MO has agreed to start Keytruda and submitted the request to the insurance company. She also said another option would be to start Keytruda only when hormone therapy fails.
Is PD-L1 negative/positive status important? I am PD-L1 negative.
If I start now, I can stop in case of severe side effects or disease progression. But if neither happens, how long should I stay on Keytruda?
What do you all think? Any input will be much appreciated. TIA.
PS- It's time to say Happy New Year (to the extent possible) to all of you brave warriors!!
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"She also said another option would be to start Keytruda only when hormone therapy fails." I would do that. Even when you have the mutations which make you eligible for Keytruda, it frequently turns out to be not effective. If it works you can stay on it while it works.
In a way, you may have just won the lottery! For those few who have msi-hi/dMMR, Keytruda usually works almost miraculously. I agree with your MO who said to drop all other therapies and just use Keytruda. If it doesn't work, and you'll know soon, you can always go back to the hormone therapy.
For MSI-hi/dMMR, Keytruda works independently of PD-L1 status.
my only council is to taper off the prednizone and not stop it cold turkey. It is a wonderful drug but stopping all of a sudden really shocks the body.
I came across this study regarding side effects of Pembrolizumab. About 50% of the treated patients had severe side effects i.e. Grade 3-5 events: sciencedirect.com/science/a...
Thank you GP24 for the great article. The 50% figure you referred to is a little scary indeed. At the same time the study says "Only a small proportion of patients discontinued treatment due to toxicity in this analysis (12.7% because of all-cause AEs and 3.6% because of immune-mediated AEs or infusion reactions)".
Thank you, I really appreciate your support. BTW it would be interesting to know how the MSI-high patients fared (4% of patients had MSI- high cancers).
The trials with Pembrolizumab were done in castration-resistant patients and you wrote: "I have mHSPC and the last PSA was <0.05 (“Undetectable”) for the first time in my journey." It is unknown how effective Pembrolizumab is in HSPC. There is a trial now to find out: tandfonline.com/doi/10.2217...
With this information, I do not understand why your MO wants to start you on Pembrolizumab. I did not check, but the guidelines will recommend Pembrolizumab für CRPC with your mutations. With your currently undetectable PSA you could avoid the side effects of Pembrolizumab and continue with your hormone therapy. I would say, Pembrolizumab cannot achieve more than an undetectable PSA value.
Thanks GP24. I believe less than 1% of advanced PC patients are MSI-high. Any study or trial that does not focus on MSI-high status is probably not very relevant to my case at this point. I will take the risk of side effects and see if I can get a durable response.
We will try to use the Guardant 360 Response test and ctDNA counts to get a feel for the effectiveness of Pembro. This seems to be the best we can do.
One of the MO's said, if you are fighting an enemy and he is on the floor, then kick it, don't allow him to get up. So we will kick.
You're absolutely correct—Keytruda (pembrolizumab) has not been conclusively proven to be effective in the hormone-sensitive phase of advanced prostate cancer. Most of the available data on Keytruda pertains to castration-resistant prostate cancer (CRPC), particularly in patients with specific biomarkers like microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). The lack of evidence for its use in the hormone-sensitive phase raises important considerations for its timing and integration into treatment.
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Why We Don’t Know if Keytruda is Effective in the Hormone-Sensitive Phase
1. Limited Research in Hormone-Sensitive Prostate Cancer (HSPC):
Most studies on Keytruda have focused on advanced prostate cancer in the castration-resistant setting because this is where treatment options are most limited.
In the hormone-sensitive phase, standard therapies like androgen deprivation therapy (ADT) with or without next-generation agents (e.g., enzalutamide, abiraterone) have well-documented efficacy, making Keytruda an untested option in this earlier phase.
2. Tumor Microenvironment in HSPC:
Hormone-sensitive prostate cancer generally has a "cold" immune microenvironment, meaning it lacks the immune cell infiltration and PD-L1 expression that would make it more responsive to immune checkpoint inhibitors like Keytruda.
3. Ongoing Trials:
Some clinical trials are exploring the use of immune checkpoint inhibitors in combination with hormone therapy in hormone-sensitive settings, but results are not yet conclusive. These trials aim to determine if hormonal manipulation can increase tumor immunogenicity and improve response to immunotherapy.
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Potential Benefits and Risks of Using Keytruda in HSPC
Potential Benefits:
1. Immune Priming:
In theory, introducing Keytruda during the hormone-sensitive phase might prime the immune system to attack the cancer while the disease is less aggressive and the tumor burden is lower.
Some preclinical studies suggest that androgen deprivation therapy (ADT) can enhance T-cell activity, potentially creating a more favorable environment for immunotherapy.
2. Preventing Early Resistance:
Immune checkpoint inhibitors could target resistant clones earlier, potentially delaying the onset of castration resistance.
Potential Risks:
1. Ineffectiveness:
Without biomarkers (e.g., MSI-H or dMMR), the likelihood of Keytruda being effective in HSPC is low, potentially exposing patients to unnecessary side effects without clear benefit.
2. Toxicity:
Keytruda can cause immune-related adverse events, including pneumonitis, colitis, or endocrinopathies, which may outweigh potential benefits if the cancer is still controllable with hormonal therapy.
3. Loss of a Later Option:
Using Keytruda in the hormone-sensitive phase might lead to immune tolerance or resistance, making it less effective when the disease progresses to the castration-resistant phase.
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Current Standard of Care for HSPC
For hormone-sensitive prostate cancer, the standard of care remains:
2. Combination with Next-Generation Agents: Adding drugs like enzalutamide, abiraterone, or docetaxel has been shown to improve overall survival in metastatic hormone-sensitive prostate cancer (mHSPC).
3. Reserve Immunotherapy for Specific Subgroups:
Keytruda or other immunotherapies are typically reserved for metastatic castration-resistant prostate cancer (mCRPC) in patients with biomarkers predictive of response.
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Key Ongoing Research
Several trials are investigating the combination of Keytruda with standard therapies in both hormone-sensitive and castration-resistant prostate cancer. Some promising areas include:
1. Combination with ADT or Abiraterone:
Exploring whether hormonal therapy can enhance the immune response to Keytruda.
2. Biomarker-Driven Approaches:
Identifying subgroups of HSPC patients who might benefit from immunotherapy earlier in their disease course (e.g., MSI-H/dMMR or high PD-L1 expression).
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Conclusion
At present, there is no strong evidence to support using Keytruda in the hormone-sensitive phase of prostate cancer. The most prudent strategy would be to:
1. Use standard hormone therapies first in hormone-sensitive prostate cancer, as they are proven to be effective and are the backbone of treatment.
2. Reserve Keytruda for castration-resistant disease, particularly in patients with biomarkers like MSI-H, dMMR, or high tumor mutational burden (TMB), where it is more likely to provide benefit.
3. Consider participation in clinical trials if available, especially trials investigating the role of immunotherapy in hormone-sensitive disease.
This approach ensures that Keytruda remains a viable option for later stages of disease progression, where it might be most impactful. Always consult with your oncologist to tailor treatment to your specific situation and biomarkers.
What I don't understand is what would be a benefit of keytruda early if a hormone therapy is effective? You will get added toxicity unnecessarily without any benefits plus the cancer will become resistant and then you will unnecessarily lose your weapon for a CRPC phone.
The result you provided—MMR deficiency, MSI-High, and TMB High with 34 mutations/Mb—is extremely favorable for the potential efficacy of Keytruda (pembrolizumab) in treating advanced prostate cancer. Here’s a breakdown of why this result is significant and how favorable it is:
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1. MMR Deficiency (Mismatch Repair Deficiency)
What It Means: MMR-deficient tumors have defects in the DNA repair machinery, leading to an accumulation of mutations. This results in the production of neoantigens, which can make the cancer more recognizable to the immune system.
Relevance to Keytruda: Tumors with MMR deficiency are known to respond well to immune checkpoint inhibitors like Keytruda, as these drugs enhance the immune system's ability to target and destroy cancer cells with high mutation burdens.
2. MSI-High (Microsatellite Instability-High)
What It Means: MSI-High tumors are characterized by numerous small mutations in repetitive DNA sequences. This is another marker of genomic instability often associated with MMR deficiency.
Relevance to Keytruda: The FDA has approved Keytruda for any MSI-High solid tumor, regardless of its location in the body, because these tumors have consistently shown responsiveness to immune checkpoint inhibitors.
3. TMB High (Tumor Mutational Burden)
What It Means: A TMB of 34 mutations/Mb is well above the typical cutoff for TMB-High (usually defined as ≥10 mutations/Mb). High TMB indicates a large number of mutations, which increases the likelihood of generating neoantigens that immune cells can target.
Relevance to Keytruda: TMB-High status is another predictor of responsiveness to immunotherapy, as it suggests the tumor is more likely to be recognized and attacked by the immune system.
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How Favorable Is This Result for Keytruda?
1. Strong Predictors of Response:
MMR deficiency, MSI-High, and TMB-High are all well-established biomarkers that predict robust responses to immune checkpoint inhibitors like Keytruda.
Studies have shown that patients with these biomarkers often experience durable responses, including long-lasting remission, even in aggressive and advanced cancers.
2. FDA Approval Based on These Biomarkers:
Keytruda is specifically approved for tumors with these biomarkers, making this result highly favorable for its use in your case.
3. Prostate Cancer Context:
While most prostate cancers are not MSI-High or MMR-deficient, the subset that exhibits these characteristics tends to respond exceptionally well to immunotherapy, unlike the majority of prostate cancers that are typically resistant to these treatments.
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Expected Outcomes with Keytruda in This Setting
High Response Rates: Patients with MMR deficiency, MSI-High, and/or TMB-High typically have significantly higher response rates to Keytruda than those without these markers.
Durable Responses: Immunotherapy in this context often leads to durable control of the disease, even in metastatic or advanced cases.
Potential for Prolonged Survival: Many patients with these biomarkers have shown prolonged survival when treated with immune checkpoint inhibitors.
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Conclusion
The result of MMR deficiency, MSI-High, and TMB-High (34 mutations/Mb) is highly favorable for the use of Keytruda. This combination of biomarkers is rare in prostate cancer but represents one of the best-case scenarios for immunotherapy responsiveness. Discuss with your oncologist about starting Keytruda promptly, as these findings strongly support its potential to provide significant benefit in your case.
Replacing an effective hormonal therapy with Keytruda (pembrolizumab) in the hormone-sensitive phase of prostate cancer is a complex decision. While the results of MMR deficiency, MSI-High, and TMB-High (34 mutations/Mb) strongly predict responsiveness to Keytruda, this does not automatically mean it should replace hormonal therapy at this stage. Here's a detailed analysis:
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Reasons to Be Cautious About Replacing Hormonal Therapy
1. Proven Efficacy of Hormonal Therapy in HSPC:
Hormonal therapy (e.g., androgen deprivation therapy with or without abiraterone or enzalutamide) is the cornerstone of treatment for hormone-sensitive prostate cancer (HSPC). It reliably reduces tumor burden, delays disease progression, and improves survival.
Hormonal therapy acts quickly to control symptoms and PSA levels, which may not occur as rapidly with immunotherapy.
2. Lack of Evidence for Keytruda in HSPC:
Keytruda has been studied and approved primarily for metastatic castration-resistant prostate cancer (mCRPC) in biomarker-positive patients. There is little to no clinical trial data supporting its use as a monotherapy in the hormone-sensitive setting.
The immune system’s ability to respond to immunotherapy might not be fully activated during the hormone-sensitive phase, as the tumor microenvironment is often less inflamed at this stage.
3. Loss of a Proven Treatment Option:
Replacing hormonal therapy with Keytruda might risk losing the benefits of a treatment known to work reliably in the hormone-sensitive phase.
4. Immune Response May Be Better Post-ADT:
Hormonal therapy (e.g., ADT) can enhance T-cell activity and increase immune cell infiltration in the tumor, potentially making immunotherapy more effective when used after ADT or in combination.
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Arguments for Considering Keytruda Early
1. Exceptional Biomarker Profile:
The combination of MMR deficiency, MSI-High, and TMB-High is rare in prostate cancer and strongly predicts a high likelihood of response to Keytruda. This makes early use of immunotherapy more justifiable in your case than for most patients.
2. Potential for Durable Responses:
If Keytruda induces a strong immune response, it may provide prolonged disease control, potentially sparing the need for ongoing hormonal therapy and its associated side effects (e.g., fatigue, bone loss, metabolic changes).
3. Avoiding Long-Term Hormonal Therapy Toxicity:
Hormonal therapy is associated with significant side effects that accumulate over time. If Keytruda achieves a durable response, it could reduce reliance on hormonal therapy.
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Optimal Strategy: Combining or Sequencing Therapies
Rather than replacing hormonal therapy entirely, it might be better to consider one of the following approaches:
Rationale: Combining Keytruda with ADT or next-generation hormonal agents (e.g., enzalutamide) might provide a synergistic effect by enhancing the immune response while maintaining hormonal suppression of the cancer.
Evidence: While not yet proven in prostate cancer, combination approaches are being explored in clinical trials. In other cancers (e.g., lung cancer), combining immunotherapy with other modalities has shown significant benefits.
2. Sequential Therapy: Hormonal Therapy Followed by Keytruda
Rationale: Start with hormonal therapy to achieve rapid control of the cancer and delay progression, then introduce Keytruda once the cancer becomes less hormone-sensitive or resistant.
Advantage: This ensures the tumor is controlled while preserving Keytruda as an option for later, when the tumor microenvironment might be more primed for immunotherapy due to prior hormonal manipulation.
3. Keytruda as First-Line Monotherapy (Only for Exceptional Cases)
Rationale: In rare cases where the biomarker profile strongly predicts a response and hormonal therapy is poorly tolerated or not preferred, Keytruda could be used upfront. However, this approach is experimental and should ideally be done in a clinical trial setting.
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Conclusion
While your biomarker profile (MMR deficiency, MSI-High, TMB-High) is highly favorable for Keytruda, replacing effective hormonal therapy entirely in the hormone-sensitive phase is not currently supported by evidence. A more balanced approach would involve either combining Keytruda with hormonal therapy or using hormonal therapy first and reserving Keytruda for later stages.
Discuss these options with your oncologist, considering factors such as:
The urgency of tumor control.
Your overall health, preferences, and tolerance for treatment side effects.
Access to clinical trials combining hormonal therapy and immunotherapy.
Thank you Seasaid, I so appreciate the effort you put into looking into this complex situation. There is certainly a lot to think about. For me one of the most important aspects is: “3. Loss of a Later Option: Using Keytruda in the hormone-sensitive phase might lead to immune tolerance or resistance, making it less effective when the disease progresses to the castration-resistant phase.”
I asked ChatGPT about this and I got: “In conclusion, while the concern about inducing immune tolerance or resistance by using Keytruda early in the treatment of hormone-sensitive metastatic prostate cancer is thoughtful, it is not fully supported by clear clinical evidence to warrant avoiding its use, especially in the presence of strong predictors of response like MSI-H, MMR deficiency, and high TMB. The decision should be tailored to individual patient conditions and should involve close monitoring and flexibility in treatment planning to address the evolving nature of the disease.”
Another aspect: “Optimal Strategy: Combining or Sequencing Therapies
Rather than replacing hormonal therapy entirely, it might be better to consider one of the following approaches:
I would do the same. Do only reason to stop hormone therapy would could be to conduct an experiment on you.
With parallel (hybrid) approach you will reap the benefits of the immuno therapy and in a same time you will enjoy the safety of the standard of care for hormone sensitive phase of your disease.
The only problem for you could be the added toxicity of two parallel treatments but actually you will enjoy the safety of the approach because you could safely stop keytruda if you present with side effects higher grade.
I agree with your decision and wish you all the best. If you have any questions just contact this forum.
I didn't look into the offered clinical trials of keytruda in a hormone sensitive phase but I believe that they will not want you to continue with hormonal therapy. (I don't really know but it is worth checking if you have a time.
I was considering the sbrt of my metastasis in a setting of a Bayer clinical trial for darolutamide (Nubeqa) for none metastatic castrate resistant prostate cancer (nmCRPC) plus SBRT on the PSMA pet scan visible metastasis. (Maybe I wasn't even eligible because I don't have any on any scans visible metastasis).
And the MRI Linac radiation oncologist said that they are also taking part in that clinical trial but the high precision MRI Linac Elekta Unity machine will not be used in that clinical trial.
My point is that blindly believing that you are doing a best for yourself by taking part in a clinical trial maybe not always true. It depends on your situation and what they offer
I believe that the clinical trials are designed not for your best benefit but to approve a drug.
Ask for second opinion as TA suggest if you want.
I like that if keytruda will do miracles to you than you will not miss it by introducing immunotherapy in an early stage but if you develop high toxicity you could always stop because you are still under the standard of care for your hormone sensitive phase.
Thank you for sharing your thoughtful reflections and the feedback from the forum. It’s clear you’ve taken the time to carefully weigh the pros and cons of early immunotherapy in hormone-sensitive metastatic prostate cancer, as well as the potential combination strategy with hormonal therapy.
Your points, particularly on the synergy of combining Keytruda with hormone therapy and the flexibility of discontinuing Keytruda if toxicity arises, align with a cautious but proactive approach. This strategy preserves the benefits of standard care while exploring the potential advantages of immunotherapy, especially given predictors of response like MSI-H, MMR deficiency, or high TMB.
The discussion also highlights important considerations around clinical trials:
1. Clinical Trial Design: Trials are designed to generate data for drug approval, and while participants may benefit, trial protocols might not always align perfectly with individual needs. Evaluating the trial specifics, including eligibility and treatment approaches, is essential.
2. Second Opinions: Consulting additional specialists can provide insights tailored to your unique case, particularly when considering cutting-edge or experimental therapies.
3. SBRT and Clinical Trials: It’s interesting to hear about the darolutamide trial combined with SBRT. While your situation may differ, the inclusion of SBRT highlights an evolving treatment paradigm aimed at precise targeting of metastases, even in earlier disease stages.
Your strategy of integrating Keytruda early, coupled with hormonal therapy, seems pragmatic. It allows you to explore the benefits of immunotherapy while maintaining the backbone of standard treatment, providing a safety net in case challenges arise.
If you'd like to explore any specific clinical trials further or dive deeper into immunotherapy sequencing strategies, I’d be happy to assist. Wishing you all the best as you navigate these decisions, and feel free to reach out for further insights or support!
TA recommendations about having multiple doctors in your care:
"Some hospitals offer a team approach - sort of like one-stop shopping. All their best experts give you their opinions. Ideally, you would want to pick your own best doctors, but if you belong to an HMO, that may not be possible. If you have to have a team approach, it is best if you meet with each team member separately. Doctors are often reluctant to contradict or disagree with one another in the same room."
I found a small study reporting how effective pembrolizumab is: pubmed.ncbi.nlm.nih.gov/383... I read: "The ORR (overall response rate) was 50% (27.3% complete response and 22.7% had partial response)" With other words, half of the patients did have no benefit from this treatment.
one user told me in this group or other group that His MO send biopsy to Keytruda and they make a sure that Keytruda going to work or not ? Also combine target therapy base on it
Not sure if you already searched this site for other keytruda experiences, but there are at least three of us on this site with durable (miraculous) keytruda responses. My husband is one of them. He was only able to tolerate one infusion but his cancer has been undetectable ever since. That was almost three years ago. I believe that all three with durable responses were castrate resistant prior to starting the infusions though. You have a tough decision to make. Wishing you well.
Thank you dico. Yes I searched and I saw your husband's case which was remarkable in that he couldn't tolerate the treatment yet the same treatment was super effective. So happy it worked out great for him. May the cancer never return!
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Genetic test 
Xgeva for bone metastisis
Appointment with MO what to do after abiraterone ( other version of zytiga )
Got my genomic analysis - sounds like there are possibilities?
