Combination Therapies for Metastatic Prostate Cancer

(KNIGHTS Trial)

Overseen By Phuoc Tran, MD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Maryland, Baltimore

Must not be taking: PARP inhibitors, Antiretrovirals

Disqualifiers: Castration-resistant prostate cancer, Uncontrolled hypertension, Active malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

88 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for individuals with recurrent metastatic prostate cancer, where cancer spreads beyond the prostate to other body parts. Researchers aim to determine if adding a combination of pills (niraparib and abiraterone acetate) to standard hormone therapy (androgen deprivation therapy, or ADT) and targeted radiation improves outcomes. Participants should have a specific genetic mutation linked to prostate cancer and have experienced cancer spreading to a few areas outside the prostate. This trial may suit those whose prostate cancer has recently spread and who seek new treatment options. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, long-term use of systemically administered corticosteroids is not allowed, and certain medications that interfere with the study drugs may also be restricted. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining hormone therapy (ADT) with targeted radiation (SABR) effectively treats prostate cancer. This combination has been proven to extend patients' lives, though it may cause side effects like tiredness and changes in sexual function.

Studies have also tested the addition of two drugs, niraparib and abiraterone acetate, to ADT and SABR for safety and effectiveness. Patients using this combination reported significant improvements in their condition. However, like many cancer treatments, it can cause side effects such as nausea and high blood pressure.

Both treatment options are used in medical settings, and researchers closely monitor their safety. It is essential to consult healthcare professionals to understand what these treatments might mean for individual patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these combination therapies for metastatic prostate cancer because they introduce innovative approaches to enhance current treatments. Unlike traditional androgen deprivation therapy (ADT) alone, these therapies incorporate stereotactic ablative radiation to precisely target cancer cells, potentially improving effectiveness. Additionally, one arm includes the use of niraparib, a PARP inhibitor, and abiraterone acetate, which could offer a new mechanism to reduce tumor growth by interfering with cancer cell repair and hormone pathways. This multi-pronged approach aims to provide more comprehensive control over the disease, offering hope for better outcomes in patients with metastatic prostate cancer.

What evidence suggests that this trial's treatments could be effective for metastatic prostate cancer?

This trial will compare two treatment combinations for metastatic prostate cancer. One group of participants will receive androgen deprivation therapy (ADT) combined with stereotactic ablative radiation (SABR). Research has shown that this combination effectively treats prostate cancer. ADT lowers hormone levels that help cancer cells grow, while SABR uses precise, high-dose radiation to target and kill these cells. ADT also prevents cancer cells from repairing themselves after radiation, and studies have found that this combination can improve survival rates for prostate cancer patients.

Another group in this trial will receive ADT and SABR along with the drugs niraparib and abiraterone acetate. This combination is promising and approved for certain types of prostate cancer, working by blocking pathways that cancer cells need to survive. Research indicates that these treatments are especially effective for prostate cancer with specific genetic mutations. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for individuals with recurrent metastatic prostate cancer, specifically those who have a small number of secondary tumors (oligometastatic). Participants should be suitable for hormonal therapy and targeted radiation (SABR), but details on specific inclusion and exclusion criteria are not provided.

Inclusion Criteria

Able to swallow the study medication tablets whole

Bone scan within 6 months of enrollment

PSA > 0.5 but <50 at enrollment

Exclusion Criteria

Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned first dose of study medication

Participants who have had the following ≤28 days prior to randomization

I've had radiation on the same spot where my cancer is now, preventing more radiation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard of care treatment with hormonal therapy and Stereotactic Ablative Radiation (SABR) or standard of care plus 6-months of niraparib/abiraterone acetate and prednisone

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including PSA evaluation and quality-of-life assessments

18 months

Long-term follow-up

Participants are monitored for progression-free survival and treatment-related adverse events

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Androgen deprivation therapy (ADT)
• Niraparib/Abiraterone Acetate
• Prednisone
• Stereotactic ablative radiation therapy (SABR)

Trial Overview The study compares standard treatment (hormonal therapy + SABR) to the same standard care plus a 6-month course of niraparib/abiraterone acetate pills and prednisone. The goal is to see if adding these medications improves outcomes.

How Is the Trial Designed?

Group I: Androgen deprivation therapy + Stereotactic ablative radiation Active Control 2 Interventions

Group II: Androgen deprivation therapy + Stereotactic ablative radiation + niraparib/abiraterone acetate Active Control 3 Interventions

Androgen deprivation therapy (ADT) is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in United States as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Canada as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Japan as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Switzerland as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Janssen Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Joaquin Duato

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

In a study involving 1974 men with high-risk non-metastatic prostate cancer, combination therapy with abiraterone acetate and prednisolone significantly improved metastasis-free survival compared to androgen-deprivation therapy (ADT) alone, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of metastasis.

The combination therapy also showed significant improvements in overall survival, prostate cancer-specific survival, and biochemical failure-free survival, although it was associated with a higher incidence of grade 3 or higher adverse events, such as hypertension and liver enzyme elevation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Attard, G., Murphy, L., Clarke, NW., et al.[2023]

Both docetaxel combined with androgen deprivation therapy (ADT) and abiraterone acetate with prednisone/prednisolone plus ADT have been shown to improve survival rates in patients with metastatic castration-naive prostate cancer.

The choice between these treatments should be personalized based on the individual characteristics of the patient, ensuring the best possible outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Castration-naive Metastatic Prostate Cancer. Hamilou, Z., Baciarello, G., Fizazi, K.[2019]

Adding abiraterone acetate plus prednisone/prednisolone (AAP) to androgen deprivation therapy (ADT) significantly reduces the risk of death in men with metastatic hormone-sensitive prostate cancer (mHSPC) by 38%, translating to a 14% absolute improvement in overall survival over three years, based on data from two major trials involving 82% of participants.

The addition of AAP also leads to a 55% reduction in the risk of clinical or radiological progression-free survival, with a 28% absolute improvement at three years, although there is an increased risk of certain grade III-IV toxicities, particularly cardiac and hepatic, without an increase in overall mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis. Rydzewska, LHM., Burdett, S., Vale, CL., et al.[2023]

In a systematic review of randomized controlled trials involving newly diagnosed patients with metastatic hormone-sensitive prostate cancer, the combination of abiraterone acetate (AA), prednisone (P), and androgen deprivation therapy (ADT) showed a 72% to 87% probability of improving overall survival compared to docetaxel (DOC) plus ADT.

The AA + P + ADT regimen not only reduced the risk of disease progression more effectively (with a 93%-97% probability) but also improved quality of life for patients, particularly noticeable within the first three months of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis. Feyerabend, S., Saad, F., Li, T., et al.[2019]

In the final analysis of the LATITUDE study involving 1199 men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer, the combination of abiraterone acetate plus prednisone with androgen deprivation therapy (ADT) significantly improved overall survival, with a median of 53.3 months compared to 36.5 months for the placebo group.

The treatment had a manageable safety profile, with common grade 3-4 adverse events including hypertension and hypokalaemia, indicating that while there are risks, the benefits of improved survival support the use of this combination therapy as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Fizazi, K., Tran, N., Fein, L., et al.[2020]

Abiraterone acetate combined with prednisone significantly improves overall survival (34.7 months vs 30.3 months) and radiologic progression-free survival (16.5 months vs 8.3 months) in patients with metastatic castration-resistant prostate cancer compared to placebo.

The treatment is generally well-tolerated, with manageable side effects primarily related to mineral corticoid excess, and it also enhances the perceived quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Abiraterone in castration resistant prostate cancer.] Juárez Soto, A., Caballero Cobos, R., Campanario Pérez, R., et al.[2018]

In a real-world study involving 1108 patients with metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate plus prednisone (AAP) was found to be effective as both first-line and second-line treatment, with median overall survival of 27.1 months for first-line and 23.4 months for second-line therapy.

The treatment was well tolerated across all patient subgroups, including those with cardiovascular comorbidities, and no unexpected adverse events were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Safety and Efficacy Outcomes with Abiraterone Acetate Plus Prednisone or Prednisolone as the First- or Second-Line Treatment for Metastatic Castration-Resistant Prostate Cancer: Data from the Prostate Cancer Registry. Bjartell, A., Lumen, N., Maroto, P., et al.[2021]

In a study of 68 patients with metastatic castration-resistant prostate cancer (mCRPC), treatment with abiraterone acetate (AA) plus prednisone (P) alone showed a comparable rate of radiographic progression-free survival (rPFS) to those continuing androgen deprivation therapy (ADT) alongside AA + P, suggesting that ADT may not be necessary.

Both treatment groups experienced moderate to severe adverse events, with 72% in the ADT group and 85% in the AA + P only group, indicating that while AA + P is effective, it is also associated with significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial. Ohlmann, CH., Jäschke, M., Jaehnig, P., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6043751/

Adjuvant androgen deprivation therapy for prostate cancer ... Current evidence suggests that androgen deprivation synergistically works with radiation therapy by preventing DNA repair.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1879850023002345

Long-Term Outcomes Following Fairly Brief Androgen ... There is limited data on the long-term outcomes of ultrahypofractionated radiation therapy in high-risk prostate cancer.

3. ascopubs.org ascopubs.org/doi/10.1200/EDBK_433126

Balancing Hormone Therapy: Mitigating Adverse Effects of ... Treatment advances including ADT have led to improvements in PCa management and survival, with trials reporting median survival of over 6 years ...

4. redjournal.org redjournal.org/article/S0360-3016(23)06060-1/fulltext

Long-Term Outcomes Following Fairly Brief Androgen ... The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-09091

A Study of Two Different Radiotherapy Treatment ... Androgen deprivation therapy lowers the amount of androgen made by the body. This may help stop the growth of tumor cells that need androgen to grow. SBRT is a ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2405630824000107

Enhancing Androgen Deprivation Therapy (ADT ... Ongoing debate surrounds ADT use with SBRT and BT in prostate cancer treatment. Trends favor less ADT, but its omission may risk outcomes.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05717660

Study Details | NCT05717660 | APalutamiAPalutamide and ... Final results from TITAN trial showed that apalutamide plus ADT improved OS in a population of patients with metastatic hormone sensitive prostate cancer ...

8. urotoday.com urotoday.com/recent-abstracts/urologic-oncology/prostate-cancer/147436-long-term-outcomes-following-fairly-brief-androgen-suppression-and-stereotactic-radiation-therapy-in-high-risk-prostate-cancer-update-from-the-fastr-fastr-2-trials-beyond-the-abstract.html

Update from the FASTR/FASTR-2 Trials Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the ...