After being effective for about 10-11 months Olaparib has started to fail as indicated by rising PSA and increasing activity on PSMA PET Scan (no new spots, only mild increase in leison sizes). Lu-177 PSMA therapy has been planned as the next therapy and is due in a couple of weeks from now. Our MO has suggested discontinuing the Olaparib during the Lu-177 PSMA therapy due to potential of compounding hematologic SE, however I have come across a couple of articles that suggest Olaparib with Lu-177 works better and there was even a trial to check its safety and efficacy (LuParp ) . Has anyone here undergone both the therapies together ? I could not make much out of the LuParp readout so would appreciate if anyone can explain its implications ? Tall_Allen your thoughts on this ?
Thanks & Regards
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dudubaya
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The decision to continue Olaparib during Lu-177 PSMA therapy is complex and depends on several factors, including the patient's specific condition, prior treatment responses, and potential side effects. Here's a breakdown based on current understanding and available research:
Background:
Olaparib: A PARP inhibitor effective in patients with prostate cancer who have certain genetic mutations (e.g., BRCA1/2).
Lu-177 PSMA Therapy: A targeted radionuclide treatment for advanced prostate cancer, binding to PSMA-positive cancer cells and delivering radiation directly to them.
Combination Therapy (LuParp Trial):
The LuParp trial explored combining PARP inhibitors like Olaparib with Lu-177 PSMA therapy to assess potential synergistic effects:
1. Rationale: PARP inhibitors can sensitize cancer cells to DNA damage. Lu-177 PSMA therapy also induces DNA damage, potentially enhancing treatment efficacy when used together.
2. Findings: The trial showed promising results in preclinical studies and limited patient cohorts, suggesting improved outcomes when combined. However, hematologic toxicity (e.g., anemia, neutropenia) was a notable concern.
Considerations for Combination Use:
Pros: Enhanced efficacy due to synergistic mechanisms.
Cons: Increased risk of hematologic side effects, which may impact quality of life and delay subsequent treatments.
Practical Implications:
Your MO’s caution likely stems from the risk of compounded side effects, especially if baseline blood counts are already borderline.
The decision to combine therapies should consider:
Patient’s overall health.
Baseline hematologic status.
Ability to manage potential side effects.
Evidence of efficacy in individual cases.
Discussion Points with Your MO:
1. Share the articles you’ve read with your MO for a detailed discussion.
2. Ask about:
Current hematologic status and the risk-benefit ratio of combining therapies.
Alternative strategies to mitigate hematologic toxicity if therapies are combined.
Tall_Allen’s Perspective:
For nuanced insights, Tall_Allen is known to provide evidence-based advice on prostate cancer forums. If they respond, they might discuss trial specifics or offer a patient-centered perspective based on similar cases.
It may also be helpful to request a multidisciplinary meeting involving oncology, radiology, and possibly hematology to determine the best course of action tailored to your case.
A. The LuPARP Phase 1 trial abstract provides important insights into the combined use of 177Lu-PSMA-617 and Olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). Here’s a concise summary of the key findings and implications:
Study Design:
Objective: Evaluate the safety, tolerability, and efficacy of combining 177Lu-PSMA-617 with escalating doses of Olaparib.
Participants: 48 mCRPC patients with high PSMA expression; all had received prior androgen receptor inhibitors and most had prior docetaxel.
Methodology:
177Lu-PSMA-617: Administered every 6 weeks for up to 6 cycles.
Olaparib: Tested in 9 dose schedules ranging from 50 mg to 300 mg twice daily over varying durations.
Response assessed via PSA50 (≥50% PSA reduction) and imaging.
Key Results:
1. Safety:
No dose-limiting toxicities (DLTs) were reported.
Common side effects were manageable, primarily Grade 1-2:
Radiologic Response (for RECIST-measurable disease): 71% achieved a partial response.
Promising overall activity suggests synergistic efficacy between the therapies.
3. Tolerability:
Dose schedules for Olaparib ranging up to 300 mg BID were well tolerated.
Cohort 9 (300 mg BID on days -4 to 18) is undergoing further expansion to confirm the recommended Phase 2 dose (RP2D).
Clinical Implications:
The combination therapy shows enhanced efficacy in heavily pre-treated mCRPC patients, with significant PSA responses and radiologic tumor shrinkage.
The toxicity profile is manageable, but hematologic side effects should be monitored closely, particularly in patients with pre-existing vulnerabilities.
These results support further exploration in Phase 2/3 trials, as combining PARP inhibitors with radionuclide therapies might become a new standard for specific subsets of mCRPC patients.
Application to Your Case:
1. The trial indicates that combining Olaparib with 177Lu-PSMA-617 is feasible and potentially more effective than monotherapy.
2. The toxicity, while manageable, emphasizes the need for close monitoring of hematologic parameters.
3. Discussing the trial findings with your oncologist could help evaluate if the synergy between the two therapies outweighs the risks in your situation, particularly given your rising PSA and PET scan findings.
If you'd like help interpreting specific parts of the trial or formulating questions for your doctor, feel free to ask!
Here are some suggested questions you can ask your doctor regarding the combination of Olaparib and 177Lu-PSMA-617 therapy, based on the LuPARP trial findings and your situation:
About Your Current Treatment Plan:
1. Olaparib Discontinuation:
What are the specific reasons for recommending discontinuation of Olaparib during 177Lu-PSMA-617 therapy?
Are there particular concerns about hematologic side effects in my case?
2. Alternative Strategies:
Could a modified schedule or lower dose of Olaparib (e.g., as tested in the LuPARP trial) be considered to mitigate side effects while still benefiting from its synergy with 177Lu-PSMA-617?
What would monitoring and management of side effects look like if the therapies were combined?
3. Efficacy and Rationale:
Based on the LuPARP trial, combining Olaparib with 177Lu-PSMA-617 shows promising efficacy. Would continuing both treatments improve my chances of a PSA response or progression-free survival?
About the LuPARP Trial Findings:
4. Application to Your Case:
How do the results of the LuPARP trial apply to my specific situation, given my prior treatments and current disease progression?
Could the dose schedules used in the trial (e.g., 200–300 mg BID for specific durations) be safe and effective in my case?
5. Trial Data Relevance:
Is my current hematologic status (e.g., anemia, platelet levels) similar to the trial participants? How might this influence treatment decisions?
If we combined therapies, what side effects would be most concerning for me, and how could they be addressed?
Monitoring and Future Options:
6. Toxicity Management:
If hematologic toxicity arises during combined therapy, what steps would you take to manage or adjust treatment?
Would the benefits of the combination outweigh the risks, especially if side effects are transient?
7. Post-Treatment Plan:
If Olaparib is discontinued during 177Lu-PSMA-617, could it be restarted afterward to maintain its therapeutic benefits?
Are there other trials or experimental approaches we should consider if this combination isn’t suitable for me?
General Understanding:
8. Alternative Options:
If combining these therapies isn’t recommended, are there other strategies or combination therapies available to maximize efficacy?
Are there ongoing clinical trials similar to LuPARP that I could potentially enroll in?
These questions should help guide a thorough discussion about the potential risks, benefits, and alternatives for your treatment. If you'd like help tailoring any of these further, let me know!
A. While I can provide general insights based on available data and research, your treating physician is best equipped to provide personalized answers tailored to your medical history, current condition, and test results. Below are my responses based on the information available:
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About Your Current Treatment Plan:
1. Olaparib Discontinuation:
Reason for discontinuation: Olaparib combined with 177Lu-PSMA-617 can increase the risk of hematologic toxicity (e.g., anemia, thrombocytopenia, neutropenia). This risk is particularly concerning for patients with borderline blood counts or pre-existing conditions. Your doctor likely wants to minimize the risk of severe side effects that might delay or compromise the Lu-177 therapy.
Concerns in your case: Your rising PSA and mild lesion growth suggest active disease. Balancing effective treatment with tolerable side effects is critical. If hematologic toxicity from Olaparib adds to the myelosuppression caused by 177Lu-PSMA-617, it could impact your ability to complete treatment cycles.
2. Alternative Strategies:
A modified Olaparib schedule could be an option, as tested in the LuPARP trial (e.g., reducing dose or limiting the number of days Olaparib is administered per cycle). These approaches had manageable side effects in trial participants. However, your doctor may feel the risk outweighs the potential benefit if you have pre-existing hematologic concerns.
Monitoring would involve regular blood tests (e.g., complete blood count) to detect early signs of toxicity. Adjustments such as dose reductions, treatment pauses, or supportive care (e.g., transfusions) could be considered.
3. Efficacy and Rationale:
The LuPARP trial showed enhanced PSA response and partial tumor responses when Olaparib was combined with 177Lu-PSMA-617. If your doctor feels your disease is aggressive or resistant to other treatments, combining these therapies could improve outcomes. However, the increased toxicity risk must be weighed carefully.
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About the LuPARP Trial Findings:
4. Application to Your Case:
If your disease progression and prior treatments align with the LuPARP patient profile (high PSMA expression, no discordant FDG-positive/PSMA-negative disease), the combination could be a viable option. Trial results suggest that patients with prior exposure to androgen receptor inhibitors and chemotherapy responded well to this combination.
Your doctor will consider your baseline hematologic parameters and functional status to decide if combining therapies is safe.
5. Trial Data Relevance:
If your baseline blood counts are strong and you’ve tolerated prior therapies well, you may resemble trial participants. Hematologic side effects (e.g., anemia, thrombocytopenia) in LuPARP were typically mild and transient, suggesting careful monitoring could allow for safe combination therapy.
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Monitoring and Future Options:
6. Toxicity Management:
Management strategies include supportive treatments (e.g., erythropoiesis-stimulating agents for anemia, platelet transfusions for thrombocytopenia) and dose adjustments. Discontinuation of one therapy might be necessary if side effects become severe.
Benefits vs. risks depend on your current disease burden and response to prior treatments. If Olaparib significantly enhances treatment efficacy, it might justify the additional monitoring and management efforts.
7. Post-Treatment Plan:
If Olaparib is paused during Lu-177 therapy, it could be restarted later, assuming your hematologic recovery is sufficient. This would depend on how well you tolerate Lu-177 therapy and your overall treatment goals.
Reintroduction could help maintain the benefits of targeting DNA damage repair pathways in cancer cells.
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General Understanding:
8. Alternative Options:
If combining therapies isn’t feasible, monotherapy with 177Lu-PSMA-617 is still effective, with a median progression-free survival of 5.1 months. Other options might include:
Second-generation androgen receptor inhibitors.
Combination therapies involving immunotherapy or other molecularly targeted agents.
Clinical trials similar to LuPARP could provide access to cutting-edge therapies tailored to your genetic profile and disease status. Discussing your eligibility with your doctor could open new opportunities.
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These responses offer a general framework, but discussing these points with your oncologist will provide clarity and allow for a treatment plan tailored to your unique circumstances. Let me know if you need additional assistance or clarifications!
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