Hello community - hoping for some guidance post-Lutetium + Olaparib for my dad, which hasn't been working and has been extremely hard on his body (has needed blood transfusions practically every other week) and his markers are all going up. This is a rather long summary but grateful for any thoughts/perspectives you may have - any suggestions?
(edited to add that we are US based)
*
USA-based 68 year old male with metastatic castration-resistant prostate cancer. He has the BRCA2 gene mutation and was first diagnosed with prostate cancer in 2015 with a Gleason 7. He has gone through many rounds of treatment, as the cancer has evolved over time. He underwent a laparoscopic radical prostatectomy in 2015, followed by hormone treatment and radiation. In late 2017, the prostate cancer metastasized to the peritoneal area.
He had 4 rounds of chemotherapy (Docetaxal/Carboplatin) in 2017, followed by Cytoreductive surgery with HIPEC in 2018. His situation improved until 2021 when the prostate cancer metastasized into the liver. This was treated with Olaparib 150mg and PSMA-targeted theranostics in Germany using Lu-177 in early 2022.
Where the tumor expressed PSMA, this led to a shrinkage of the tumor. However, at that time there were several parts of the tumor that did not express PSMA and they continued to grow. On net, the treatment combination generated only partial success. In mid 2022, the cancer was treated with Cabazitaxel, with no success. His cancer tumor markers reached the level of 21,982 for CEA, 8,908 for CA 125, 191 for CA 19-9 and 986 for LD in August 2022.
He then received a new treatment of Irinotecan 125 mg/m2 Floxuridine INU 209mg/Flat for 14 days delivered through an intra-arterial infusion pump. In late 2022, Fluororacil IVCI 1000mg/m2 for 2 days was added. The treatment worked extremely well for a period of time. By mid-2023, the CEA had fallen precipitously to 45, the CA 125 dropped to 40, CA 19-9 went to 39 and LD fell to 233.
Local radiation of a tumor close to the bowel was successfully carried out in September 2023. He recovered the weight lost following the radiation treatment.
Unfortunately, since 2023 the cancer markers started to increase. In early 2024 the readings were 267 for CEA, 178 for CA 125, 53 for CA 19-9 and 263 for LD.
In addition, the scans (PET FDG, PSMA and CT Scans) have indicated that the tumors are growing. The tumor has exhibited substantial plasticity and a PSMA PET Scan in2024 indicated that the tumors began to express considerably more PSMA than it had before. A March FDG PET Scan indicated that there was a close relation between the cancer as detected from the PSMA Scan and the FDG Scan. Thus, it was decided to restart the Lutetium 177 treatment. He has received 2 treatments with Lutetium accompanied by Olaparib. But as mentioned in the beginning of the post his markers are going up still and he is generally feeling unwell.
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BiTEs exhibit antigen spreading (the T-cells get activated by other cancer antigens than just PSMA), so they may work on the mixed type that your father has.
Edited to clarify he is US based (he did the Lutetium in Germany prior to FDA approval here). Will be on the lookout for BiTE trials in the US (will link them here in case helpful for others). Also discovered 225Ac-J591 thanks to this wonderful forum, trying to figure out why this trial was suspended: clinicaltrials.gov/study/NC...
IMO, 225Ac-j591 would be a bad idea for him because of the short-range alpha particles that will not reach his many cancer cells that do not express PSMA.
Thank you for this incredible work re: article and additional guidance/thoughts on 225Ac-j591. Encountering people like you (and this forum) restores my faith in humanity... THANK YOU x10000 💜
Learning questions - I liked the idea to target tumor without rely on PMSA expression but above clinic trial focus on Adenocarcinoma. What are other clinical trials for Metastatic Castration-resistant Prostate that do not rely on PMSA expression or other method than PSMA expression
I am not a doctor but wish to understand your situation. So you have an inherited BRCA mutation but olaparib stopped working? Do you know why is it not working?
"It seems like you're referring to a situation where someone has a BRCA mutation, possibly related to a case where the drug olaparib (a PARP inhibitor) stopped being effective. In cases like this, cancer cells can develop resistance to treatments like olaparib over time.
There are several reasons why olaparib might stop working:
1. **Secondary Mutations**: Cancer cells may acquire secondary mutations that restore the function of BRCA1 or BRCA2 genes, allowing them to repair DNA damage more effectively and become less reliant on PARP enzymes for survival.
2. **Upregulation of Alternative DNA Repair Pathways**: The cancer cells may upregulate alternative pathways for DNA repair, bypassing the need for BRCA or PARP.
3. **Increased Drug Efflux**: Cancer cells might increase the expression of drug transporters that pump olaparib out of the cells, reducing the drug's effectiveness.
4. **Loss of BRCA Function**: In some cases, even though a person has a BRCA mutation, the tumor might lose BRCA gene function entirely, which can make PARP inhibitors less effective.
It's crucial to have a detailed discussion with an oncologist to understand the specific mechanisms in play and to explore alternative treatment options, which might include other targeted therapies, chemotherapy, or clinical trials."
When olaparib stops working in the setting of metastatic castration-resistant prostate cancer (mCRPC), there are several strategies that might be considered:
### 1. **Switching to Another PARP Inhibitor**
- While olaparib is a widely used PARP inhibitor, other PARP inhibitors like rucaparib, niraparib, or talazoparib could be considered. Even though they work similarly, in some cases, switching to a different PARP inhibitor might be effective if there's partial resistance or issues with tolerance to olaparib.
### 2. **Combination Therapies**
- **PARP Inhibitors + Immune Checkpoint Inhibitors:** Some research suggests that combining PARP inhibitors with immune checkpoint inhibitors (like pembrolizumab) may be effective, particularly if the tumor has certain mutations that make it more responsive to immune therapy.
- **PARP Inhibitors + AKT Inhibitors:** Combining PARP inhibitors with AKT inhibitors might help target resistance pathways, specifically the PI3K/AKT pathway, which can be involved in resistance to PARP inhibitors.
- **PARP Inhibitors + Radiation Therapy:** Sometimes, combining PARP inhibitors with radiation therapy can enhance the effectiveness of treatment by increasing DNA damage in cancer cells, making it harder for them to survive.
### 3. **Exploring Clinical Trials**
- Participating in a clinical trial could provide access to new and experimental therapies that might be effective against mCRPC, particularly after resistance to standard treatments like olaparib has developed.
### 4. **Considering Alternative Targeted Therapies**
- Depending on the specific genetic profile of the cancer, other targeted therapies might be appropriate. For instance, if the cancer has mutations in other DNA repair genes, different inhibitors targeting those pathways could be an option.
### 5. **Chemotherapy**
- If targeted therapies are no longer effective, traditional chemotherapy might be reintroduced. Drugs like docetaxel or cabazitaxel are commonly used in mCRPC and might still provide benefit.
### 6. **Hormonal Therapies**
- Continuing with or adjusting androgen deprivation therapy (ADT) or adding other hormonal agents like enzalutamide or abiraterone could be part of the treatment strategy, depending on what has already been tried and how the cancer has responded.
### 7. **Genetic and Molecular Profiling**
- Conducting comprehensive genetic and molecular profiling of the tumor can provide insights into new treatment avenues by identifying actionable mutations or pathways that could be targeted.
It's important to discuss these options with an oncologist who can tailor the treatment approach based on the specific characteristics of the cancer and the patient's overall health.
Hello! Thank you so much for your responses and the ChatGPT help - truly appreciate you giving this time & thought. Yes, he is taking both in parallel (olaparib given the BRCA2 mutation). Not working in the sense that the cancer markers continue to go up.
Q. Hello! Thank you so much for your responses and the ChatGPT help - truly appreciate you giving this time & thought. Yes, he is taking both in parallel lutetium-177-PSMA infusions and (olaparib given the BRCA2 mutation). Not working in the sense that the cancer markers continue to go up.
A. Thank you for sharing more details. The fact that cancer markers continue to rise despite both Lutetium-177-PSMA infusions and olaparib suggests that the cancer might be developing resistance to these treatments, or that it is aggressive and not fully responsive to the current therapy combination. Here are some considerations and potential next steps:
### 1. **Evaluate the Lutetium-177-PSMA Therapy**
- **Imaging Studies**: Consider repeating PSMA PET/CT scans to assess whether Lutetium-177-PSMA is effectively targeting and reducing the tumor burden. If the scans show stable or progressing disease despite treatment, this might suggest that the therapy is not sufficiently effective on its own or that the cancer is expressing less PSMA, making it less susceptible to the treatment.
### 2. **Assessing the BRCA2-Related Resistance**
- **Genetic Testing**: Further genetic testing or biopsy might help understand whether there’s a mechanism, such as a secondary mutation in BRCA2 or activation of alternative repair pathways, that’s leading to olaparib resistance.
- **Consider Combination Therapies**: Given that olaparib alone might not be effective, combining it with other treatments like immune checkpoint inhibitors or other DNA repair-targeted therapies could potentially overcome resistance.
### 3. **Exploring Additional or Alternative Treatments**
- **Alternative PARP Inhibitors or Combination Approaches**: While olaparib is a standard treatment, other PARP inhibitors or combinations (e.g., with AKT inhibitors) might provide some benefit. Clinical trials targeting these specific mechanisms could be worth exploring.
- **Chemotherapy**: If targeted therapies are failing, chemotherapy agents like cabazitaxel, which is used in mCRPC, could be considered, potentially in combination with ongoing treatments.
- **Advanced Radiation Therapies**: If the Lutetium-177-PSMA is partially effective, it might be combined with or followed by other targeted radiation therapies to enhance its effectiveness.
### 4. **Consider Clinical Trials**
- **Investigational Therapies**: Enrolling in clinical trials that are testing new drugs or combinations of treatments could provide access to therapies that might be more effective, especially in cases where standard treatments are failing.
### 5. **Multidisciplinary Review**
- **Tumor Board Discussion**: Engaging a multidisciplinary tumor board that includes experts in medical oncology, radiation oncology, and molecular genetics could provide a broader perspective and lead to more tailored treatment strategies.
### 6. **Monitoring and Supportive Care**
- **Close Monitoring**: Continue to monitor cancer markers, imaging results, and overall health to adjust the treatment plan as needed. Supportive care to manage symptoms and maintain quality of life is also crucial.
It's a complex and challenging situation, but understanding the underlying reasons for treatment resistance and exploring alternative or combination therapies could help in finding a more effective approach. Consulting with the oncology team about these possibilities might be the best next step.
"Yes, the next steps after olaparib stops working are indeed related to understanding the specific cause of the resistance. Knowing why olaparib is no longer effective can guide more precise treatment decisions. Here's how:
### 1. **Mechanism of Resistance**
- **Secondary BRCA Mutations**: If the cancer cells develop secondary mutations that restore BRCA function, making them less dependent on PARP inhibition, alternative strategies might focus on other vulnerabilities, such as targeting alternative DNA repair pathways.
- **Upregulation of Alternative DNA Repair Pathways**: If the cancer has activated other DNA repair mechanisms, combining PARP inhibitors with drugs that block those pathways might be effective.
- **Increased Drug Efflux**: If the cancer cells are pumping out olaparib more efficiently, switching to a different PARP inhibitor or adding a drug that inhibits the efflux pumps could be considered.
### 2. **Tumor Heterogeneity**
- If the resistance is due to the presence of different clones of cancer cells with varying sensitivities, a combination of therapies targeting multiple pathways might be necessary.
### 3. **Loss of BRCA Function**
- If the cancer cells lose BRCA function entirely, making PARP inhibitors less effective, treatments might shift to chemotherapy or other agents that don’t rely on PARP inhibition.
### 4. **Specific Genetic Mutations**
- Resistance might be driven by specific mutations in the cancer’s DNA repair machinery or other pathways. Understanding these mutations can help identify other targeted therapies or combination treatments that might overcome resistance.
### 5. **Timing and Evolution**
- Resistance can develop gradually, allowing for interventions such as dose adjustments, adding sensitizers (drugs that enhance the effectiveness of PARP inhibitors), or switching treatments early when resistance signs first appear.
### 6. **Clinical Trials**
- If the exact resistance mechanism is known, a clinical trial targeting that mechanism might be the best option, providing access to new drugs or combinations that aren't yet widely available.
### 7. **Immunotherapy Consideration**
- In some cases, resistance might make the cancer more recognizable to the immune system, making it a candidate for immunotherapy, especially in combination with other agents.
By understanding the specific reason for resistance to olaparib, oncologists can more effectively tailor the next steps in treatment, potentially improving outcomes and extending the effectiveness of other therapies."
Determining why olaparib stopped working in a metastatic castration-resistant prostate cancer (mCRPC) setting involves a combination of clinical assessments, advanced diagnostic techniques, and sometimes genetic or molecular testing. Here’s how it could be done:
### 1. **Tumor Biopsy and Genetic Testing**
- **Re-biopsy of the Tumor**: A biopsy of the metastatic tumor can be performed to obtain fresh tissue. This tissue can then be subjected to next-generation sequencing (NGS) or whole-exome sequencing (WES) to identify genetic changes that might have occurred since olaparib treatment started.
- **Genetic Analysis**: Testing for secondary mutations in BRCA1/2 or other DNA repair genes that might restore homologous recombination (HR) function is crucial. This can reveal whether the cancer has developed a way to repair DNA without relying on PARP, rendering olaparib ineffective.
### 2. **Liquid Biopsy**
- **Circulating Tumor DNA (ctDNA) Testing**: Liquid biopsy involves analyzing DNA from cancer cells that are circulating in the bloodstream. This can provide information about genetic mutations or changes without needing a traditional biopsy. It can be particularly useful if a traditional biopsy is difficult or risky.
- **Monitoring Resistance Markers**: Specific genetic alterations associated with resistance to PARP inhibitors might be detected in ctDNA, helping to understand the resistance mechanism.
### 3. **Functional Assays**
- **HRD Testing**: Homologous recombination deficiency (HRD) tests can assess whether the tumor has lost its HR deficiency, which is why it was initially sensitive to PARP inhibitors. If HR function is restored, this could explain the resistance to olaparib.
- **Drug Sensitivity Testing**: Ex vivo drug sensitivity assays can sometimes be performed on biopsy samples to test how the tumor cells respond to various drugs, including other PARP inhibitors or combination therapies.
### 4. **Imaging Studies**
- **PET Scans and Other Advanced Imaging**: Imaging, especially PSMA PET scans, can help evaluate the tumor’s metabolic activity and might give clues about how the cancer is evolving. For instance, changes in tumor behavior or new areas of metastasis might suggest that the cancer has become more aggressive or resistant.
### 5. **Protein and Pathway Analysis**
- **Proteomic Analysis**: Analyzing the proteins expressed by the tumor can reveal changes in signaling pathways or protein expression that might contribute to drug resistance. For example, increased expression of drug efflux pumps or activation of alternative DNA repair pathways could be identified.
- **Pathway Activation Studies**: If specific pathways (like PI3K/AKT) are found to be activated in the tumor, this might indicate that the cancer is using alternative survival mechanisms to evade the effects of olaparib.
### 6. **Clinical Observation and PSA Trends**
- **Tracking PSA Levels**: Monitoring PSA trends can provide indirect evidence of treatment failure. A rising PSA despite ongoing olaparib treatment may indicate resistance, prompting further investigation.
- **Assessing Symptom Changes**: Any new or worsening symptoms might reflect disease progression or a change in tumor behavior, suggesting resistance.
### 7. **Review of Previous Treatments**
- **Treatment History Analysis**: Reviewing the history of previous treatments and how the cancer responded or became resistant to them might offer insights into current resistance mechanisms.
### 8. **Collaboration with a Multidisciplinary Team**
- **Molecular Tumor Boards**: In complex cases, a multidisciplinary team including oncologists, geneticists, and molecular pathologists can review the patient’s case and help decide the best approach to determine the cause of resistance.
Understanding why olaparib stopped working involves a detailed investigation of the cancer’s genetic and molecular characteristics. The results can then guide more personalized treatment decisions, potentially including switching therapies, enrolling in clinical trials, or using combination treatments tailored to overcome the specific resistance mechanisms identified.
You can also put the questions in the ChatGPT and see what will you get out and you can than ask more specific questions etc. It is almost like a learning process but be careful and do additional research because ChatGPT is not always accurate.
I don't pay but sometimes they say that they are reverting me to a simpler model, but maybe they just nodding me to pay? Usually after some time they are no restrictions. I am not the best person to ask. Install ChatGPT and ask them for more information. I do not want to pay because I am saving money for doctors.
Q. Hello community - hoping for some guidance post-Lutetium + Olaparib for my dad, which hasn't been working and has been extremely hard on his body (has needed blood transfusions practically every other week) and his markers are all going up. This is a rather long summary but grateful for any thoughts/perspectives you may have - any suggestions?
(edited to add that we are US based)
*
USA-based 68 year old male with metastatic castration-resistant prostate cancer. He has the BRCA2 gene mutation and was first diagnosed with prostate cancer in 2015 with a Gleason 7. He has gone through many rounds of treatment, as the cancer has evolved over time. He underwent a laparoscopic radical prostatectomy in 2015, followed by hormone treatment and radiation. In late 2017, the prostate cancer metastasized to the peritoneal area.
He had 4 rounds of chemotherapy (Docetaxal/Carboplatin) in 2017, followed by Cytoreductive surgery with HIPEC in 2018. His situation improved until 2021 when the prostate cancer metastasized into the liver. This was treated with Olaparib 150mg and PSMA-targeted theranostics in Germany using Lu-177 in early 2022.
Where the tumor expressed PSMA, this led to a shrinkage of the tumor. However, at that time there were several parts of the tumor that did not express PSMA and they continued to grow. On net, the treatment combination generated only partial success. In mid 2022, the cancer was treated with Cabazitaxel, with no success. His cancer tumor markers reached the level of 21,982 for CEA, 8,908 for CA 125, 191 for CA 19-9 and 986 for LD in August 2022.
He then received a new treatment of Irinotecan 125 mg/m2 Floxuridine INU 209mg/Flat for 14 days delivered through an intra-arterial infusion pump. In late 2022, Fluororacil IVCI 1000mg/m2 for 2 days was added. The treatment worked extremely well for a period of time. By mid-2023, the CEA had fallen precipitously to 45, the CA 125 dropped to 40, CA 19-9 went to 39 and LD fell to 233.
Local radiation of a tumor close to the bowel was successfully carried out in September 2023. He recovered the weight lost following the radiation treatment.
Unfortunately, since 2023 the cancer markers started to increase. In early 2024 the readings were 267 for CEA, 178 for CA 125, 53 for CA 19-9 and 263 for LD.
In addition, the scans (PET FDG, PSMA and CT Scans) have indicated that the tumors are growing. The tumor has exhibited substantial plasticity and a PSMA PET Scan in2024 indicated that the tumors began to express considerably more PSMA than it had before. A March FDG PET Scan indicated that there was a close relation between the cancer as detected from the PSMA Scan and the FDG Scan. Thus, it was decided to restart the Lutetium 177 treatment. He has received 2 treatments with Lutetium accompanied by Olaparib. But as mentioned in the beginning of the post his markers are going up still and he is generally feeling unwell.
A. It sounds like your dad has been through a lot, and I can understand how challenging it must be for both him and your family. The complexity and aggressiveness of his cancer, especially with the BRCA2 mutation and multiple treatments over the years, make this a very difficult situation. Here are some thoughts and perspectives that might help guide the next steps:
### 1. **Understanding Treatment Resistance**
- **Molecular Profiling and Re-Biopsy**: Since the cancer has shown substantial plasticity and changing PSMA expression, it might be worthwhile to do a fresh biopsy if feasible. Molecular profiling of the tumor could provide insights into why the current treatments are no longer effective. This can reveal whether there are new mutations or pathways the cancer is using to survive, which could guide further treatment.
### 2. **Consideration of Alternative Therapies**
- **Combination Approaches**: Since Lutetium-177 + Olaparib has shown limited success, exploring combination therapies might help. For example, combining PARP inhibitors like olaparib with other drugs targeting different pathways (e.g., AKT inhibitors) could potentially enhance effectiveness.
- **Immune Checkpoint Inhibitors**: Although immunotherapy hasn't been traditionally effective in prostate cancer, there may be trials or cases where it has been used successfully, particularly when combined with other treatments. Given the complexity of your dad’s case, consulting with his oncologist about trials that involve immunotherapy could be worthwhile.
- **Second Opinions**: Seeking a second opinion, especially from a cancer center that specializes in advanced prostate cancer, might uncover other treatment options or clinical trials that haven't been considered yet.
### 3. **Management of Side Effects**
- **Addressing Blood Transfusions**: The need for frequent blood transfusions indicates that his bone marrow is struggling, likely due to a combination of the cancer and the treatments. It’s important to manage these symptoms actively. Supportive care options, such as growth factors or possibly adjusting his treatment regimen to reduce toxicity, might be considered.
- **Quality of Life Considerations**: With the heavy toll that the treatments are taking on his body, there may need to be a discussion about balancing treatment intensity with quality of life. Palliative care specialists can be involved even if the primary goal is still cancer control, as they can provide interventions to manage symptoms and improve well-being.
### 4. **Exploration of Clinical Trials**
- **Accessing Experimental Therapies**: Given the advanced nature of his cancer and its resistance to multiple lines of treatment, looking into clinical trials could be a significant step. Trials might offer access to novel therapies, including new combinations of drugs, targeted therapies, or even next-generation PSMA-targeted treatments.
- **Targeted Therapy Trials**: With the BRCA2 mutation and the evolving nature of his cancer, trials focused on targeted therapies for BRCA-mutated cancers might be particularly relevant.
### 5. **Regular Monitoring and Adaptive Strategy**
- **Frequent Monitoring**: Close monitoring of his markers and imaging results is essential to adapt the treatment plan rapidly as new information becomes available. This might involve more frequent consultations with his oncology team to reassess his status and make timely decisions.
- **Adaptation Based on Response**: If the current treatment approach isn't providing the desired results, being ready to pivot to a different strategy, whether it's a new drug, a clinical trial, or a different treatment modality, is important.
### 6. **Comprehensive Care Team**
- **Interdisciplinary Collaboration**: Ensuring that his care is being managed by a comprehensive team, including oncologists, palliative care experts, genetic counselors, and possibly even experts in radiation oncology and surgical oncology, can provide a well-rounded approach to care.
### 7. **Support for You and Your Family**
- **Family Support Services**: This is a challenging time for everyone involved, and having support for the emotional and logistical aspects of his care is vital. Engaging with social workers, counselors, or support groups might help manage the stress and emotions that come with this journey.
### Conclusion
Your dad’s case is complex, and it's clear that his cancer is aggressive and has evolved over time. While his current treatment plan is not yielding the desired results, there are still options to explore, including alternative therapies, clinical trials, and perhaps re-evaluating the treatment strategy with a focus on both effectiveness and quality of life. It's also essential to keep a close dialogue with his care team and remain adaptable as new information emerges.
If you haven’t already, I would recommend bringing these ideas to his oncologist to discuss them in the context of his specific situation. Every case is unique, and sometimes a fresh perspective or new approach can make a significant difference.
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