Supportive Care Intervention for Prostate Cancer

(TOPCOP3 Trial)

Recruiting at1 trial location

Overseen by Shabbir M Alibhai, MD MSc

Age: 65+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University Health Network, Toronto

Must be taking: ARATs

Disqualifiers: Severe depression, Dementia, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial focuses on frequent health assessments and monitoring for older men with prostate cancer to identify and manage health issues early, aiming to improve patient outcomes.

Do I need to stop my current medications for this trial?

The trial does not specify if you need to stop your current medications. However, it mentions that participants should be starting or have recently started a specific type of prostate cancer medication (ARAT).

What data supports the effectiveness of the drug Lynparza (olaparib) for prostate cancer?

A phase II trial found that combining the antiandrogen abiraterone with the PARP inhibitor olaparib (Lynparza) significantly improved progression-free survival in patients with metastatic castration-resistant prostate cancer. ^{1 2 3 4 5}

Is the GA+M Intervention (Olaparib and Radium-223) safe for humans?

The combination of Olaparib and Radium-223 has been studied for safety in men with prostate cancer that has spread to the bones. Common side effects included fatigue and anemia (low red blood cell count), but it was generally considered safe at the tested doses. ^{4 6 7 8 9}

How is the GA+M, GA+RSM, and RSM drug different from other prostate cancer drugs?

The GA+M, GA+RSM, and RSM drug, known as Lynparza (also called AZD-2281, MK-7339, KU0059436), is unique because it is a PARP inhibitor, which works by blocking an enzyme used by cancer cells to repair their DNA, leading to cell death. This mechanism is different from traditional treatments like chemotherapy or hormone therapy, which target cancer cells in other ways. ^{10 11 12 13 14}

Research Team

Shabbir M Alibhai, MD MSc

Principal Investigator

UHN - Princess Margaret Cancer Centre

Eligibility Criteria

This trial is for men aged 70 or older with metastatic prostate cancer who are starting ARAT treatment. They must be able to give written consent and have a working phone. It's not for those who can't speak English, have a life expectancy under 3 months, or major neuropsychiatric issues like severe depression or dementia.

Inclusion Criteria

I am 70 years old or older.

Able to provide written informed consent

Has a working telephone

Exclusion Criteria

I do not have severe depression or moderate to severe dementia.

Unable to speak English (as contact with the nurse interventionist is via phone, not all outcome measures are available in multiple languages)

Life expectancy less than 3 months as estimated by the oncologist

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either GA+M, RSM, both interventions, or control for 6 months

6 months

Weekly symptom monitoring and follow-ups at 1, 3, and 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GA+M Intervention (Behavioural Intervention)
• GA+RSM intervention (Behavioural Intervention)
• RSM intervention (Behavioural Intervention)

Trial Overview The TOPCOP3 study tests the effectiveness of geriatric assessment and management (GA+M), remote symptom monitoring (RSM), both interventions together (GA+RSM), or neither. This pilot RCT aims to gather data on these supportive care methods to plan larger trials.

Participant Groups

Group I: RSM Intervention Active Control 1 Intervention

RSM Intervention All participants in the RSM intervention arm will receive once-weekly symptom monitoring via email-based surveys using the 9-item Edmonton Symptom Assessment Scale within a secure customized REDCap interface. If patients prefer, weekly telephone calls will be done instead by a research assistant to elicit If there are moderate or severe symptoms (score of 4+ out of 10), an oncology nurse will obtain more detailed symptom information and provide evidence-based symptom-targeted recommendations using the pan-Canadian Oncology Symptom Triage and Remote Support (COSTaRS) Practice Guide. Symptom monitoring will continue for 6 months or discontinuation of treatment.

Group II: GA+M Intervention Active Control 1 Intervention

GA+M intervention arm All participants in the GA+M intervention arm will undergo a standardized GA by a trained nurse and geriatrician. The GA will include 8 domains (comorbidity, medication review, function, falls risk, nutrition, social supports, cognition, and mood) similar to our 5C protocol. Based on any detected abnormalities or issues, a standardized set of strategies will be implemented (e.g. increased falls risk will lead to detailed assessment of balance and gait, consideration of gait aid, and referral to outpatient physiotherapy). This follows the standard approach to implementing GA similar to recent trials in geriatric oncology including 5C. Telephone follow-ups at 1, 3 and 6 months by the nurse and review with the geriatrician as needed will be done to ensure identified issues have been addressed.

Group III: GA+RSM intervention Active Control 1 Intervention

GA+RSM Combination Participants will receive both strategies as detailed above, with a GA at baseline.

Group IV: Control Active Control 1 Intervention

Control Usual care consists of brief verbal education and a drug pamphlet to all patients when starting an ARAT. There is no GA+M and no RSM at either site. Patients have access to a 24x7 oncology nursing line or a 24/7 pharmacy line.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Dr. Brad Wouters

University Health Network, Toronto

Chief Medical Officer since 2020

MD from University of Toronto

Dr. Kevin Smith

University Health Network, Toronto

Chief Executive Officer since 2018

Professor at McMaster University and University of Toronto

Findings from Research

In a study of 5,588 men with metastatic castration-resistant prostate cancer (mCRPC) in Ontario, both androgen-receptor-axis-targeted therapies (ARATs) and taxanes showed similar survival rates across first, second, and third lines of treatment, suggesting comparable efficacy.

Survival times for patients treated with ARATs were 13.0 months for first-line, 11.5 months for second-line, and 8.9 months for third-line therapy, while taxane treatments had survival times of 16.7 months for first-line, 11.3 months for second-line, and 7.8 months for third-line, indicating that both treatment types can be effective options in managing mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018. Moldaver, DM., Hassan, S., Seung, SJ., et al.[2023]

A phase II trial indicates that the combination of the antiandrogen abiraterone and the PARP inhibitor olaparib significantly enhances progression-free survival in patients with metastatic castration-resistant prostate cancer.

This benefit occurs regardless of the patients' homologous recombination repair-mutation status, suggesting a broad applicability of this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone-Olaparib Combo Aids Men with mCRPC. [2019]

In the PREVAIL study involving 872 men with metastatic castration-resistant prostate cancer, significant declines in prostate-specific antigen (PSA) levels after 3 months of enzalutamide treatment were linked to improved overall survival and progression-free survival outcomes.

Specifically, 88% of patients experienced a PSA decline of at least 30%, and greater declines were associated with longer survival and better quality of life, indicating that monitoring PSA levels can provide valuable prognostic information for treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. Armstrong, AJ., Lin, P., Higano, CS., et al.[2021]

ODM-201, a second-generation androgen receptor inhibitor, demonstrated similar pharmacokinetics between its tablet and capsule formulations, indicating that the tablet can be effectively used in treatment.

In a trial with 30 chemotherapy-naive men with metastatic castration-resistant prostate cancer, 83% showed a significant PSA response (≥50% reduction), and the treatment was well tolerated, with common side effects being fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. Massard, C., Penttinen, HM., Vjaters, E., et al.[2018]

In a study of 202 patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line androgen receptor axis-targeted therapies (ARATs), the median overall survival (OS) was not reached for those treated with ARATs alone, indicating promising survival outcomes with these therapies.

Enzalutamide showed a higher rate of PSA decline (≥90%) and longer time to nadir compared to abiraterone, suggesting it may be more effective in reducing prostate-specific antigen levels, while factors like a PSA nadir >2 ng/mL and a time to nadir <7 months were linked to shorter OS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer. Tseng, CS., Yang, JH., Huang, SW., et al.[2023]

In the ARAMIS trial, darolutamide significantly improved median metastasis-free survival by nearly 2 years and reduced the risk of death by 31% compared to placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

The overall survival benefit of darolutamide was consistent across patients with varying numbers of comorbidities and concomitant medications, with similar rates of treatment-emergent adverse events compared to placebo, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety outcomes of darolutamide in patients with non-metastatic castration-resistant prostate cancer with comorbidities and concomitant medications from the randomised phase 3 ARAMIS trial. Fizazi, K., Shore, ND., Smith, M., et al.[2023]

In the ALSYMPCA trial involving 600 patients treated with radium-223, the treatment was found to be well tolerated with a low incidence of myelosuppression and no new safety concerns reported up to 3 years after the first injection.

While 94% of radium-223 patients experienced treatment-emergent adverse events, serious hematologic issues were rare, and long-term follow-up showed no cases of acute myelogenous leukemia or myelodysplastic syndrome, indicating a favorable safety profile for radium-223 in treating symptomatic prostate cancer with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. Parker, CC., Coleman, RE., Sartor, O., et al.[2022]

The combination of olaparib and radium-223 is safe for patients with metastatic castration-resistant prostate cancer (mCRPC), with a recommended phase II dose of olaparib at 200 mg taken twice daily alongside radium-223.

Early results show promising efficacy, with a 6-month radiographic progression-free survival (rPFS) rate of 58%, particularly in patients with specific HRR gene alterations, indicating potential for further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). Pan, E., Xie, W., Ajmera, A., et al.[2023]

Abiraterone, enzalutamide, and radium-223 have been shown to significantly improve both radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC), based on phase 3 clinical trials.

Each treatment has distinct adverse effects: enzalutamide increases the risk of seizures, abiraterone can lead to mineralocorticoid excess, and radium-223 is associated with myelosuppression, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy Update for Metastatic Castration-Resistant Prostate Cancer. Dinh, JA., Baker, D., Chahal, M.[2017]

The combination of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and androgen receptor axis-targeted agents (ARAT) significantly improves radiographic progression-free survival (rPFS) by 35% in patients with metastatic castrate-resistant prostate cancer (mCRPC), especially in those with BRCA1/2 mutations, indicating a strong efficacy of this treatment approach.

While the combination therapy shows potential overall survival (OS) benefits, particularly in homologous recombination repair-mutated patients, it also leads to a significant increase in treatment-emergent adverse events (TEAEs), including a notable rise in severe anemia, suggesting that careful patient selection is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis. Sayyid, RK., Klaassen, Z., Berlin, A., et al.[2023]

In a phase 2 study involving 74 patients with metastatic castration-resistant prostate cancer, the combination of estramustine and weekly paclitaxel showed a PSA response rate of 58%, indicating significant activity against the disease.

Despite the promising PSA response, the study did not meet the primary endpoint for objective response rate, and the treatment was associated with notable toxicities, including fatigue and lymphopenia, highlighting the need for better-tolerated therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial. Wong, YN., Manola, J., Hudes, GR., et al.[2019]

Enzalutamide significantly improves overall survival and radiographic progression-free survival in men with metastatic, castration-resistant prostate cancer (mCRPC), as shown in two major randomized trials (AFFIRM and PREVAIL) involving patients who had previously undergone chemotherapy and those who were chemotherapy naive.

While enzalutamide is generally safe and effective, it can cause side effects like fatigue and has specific safety concerns, such as an increased risk of seizures and falls, particularly in older patients (≥ 75 years).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. Graff, JN., Gordon, MJ., Beer, TM.[2021]

The combination treatment of GM-CSF, ketoconazole, and mitoxantrone showed significant antitumor activity in 29 patients with castration-resistant prostate cancer (CRPC) who had previously failed docetaxel chemotherapy, resulting in a median overall survival of 18.03 months.

Patients who experienced a greater decrease in PSA levels had improved overall survival and progression-free survival, indicating that monitoring PSA levels could be a useful marker for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial assessing granulocyte-macrophage-colony stimulating factor, ketoconazole plus mitoxantrone in metastatic castration-resistant prostate cancer progressing after docetaxel treatments. Amato, RJ., Saxena, S., Stepankiw, M.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Abiraterone-Olaparib Combo Aids Men with mCRPC. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety outcomes of darolutamide in patients with non-metastatic castration-resistant prostate cancer with comorbidities and concomitant medications from the randomised phase 3 ARAMIS trial. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Therapy Update for Metastatic Castration-Resistant Prostate Cancer. [2017]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Intensification of Systemic Therapy in Addition to Definitive Local Treatment in Nonmetastatic Unfavourable Prostate Cancer: A Systematic Review and Meta-analysis. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Phase II trial assessing granulocyte-macrophage-colony stimulating factor, ketoconazole plus mitoxantrone in metastatic castration-resistant prostate cancer progressing after docetaxel treatments. [2018]