Neoadjuvant PARP Inhibition + Hormone Therapy for Prostate Cancer

(NePtune Trial)

Recruiting at 4 trial locations

Overseen By Gabrielle Tiggs

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Rana McKay, MD

Must be taking: Olaparib, LHRH agonist

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Active infection, Hepatitis, HIV, others

Stay on Your Current Meds You can continue your current medications while participating

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: 6

Duration: 6 months

32 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for some drugs. If you are taking strong CYP3A inhibitors, you need a 2-week washout period before starting the trial. If you are on strong or moderate CYP3A inducers, the washout period is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Please consult with the trial team for specific guidance on your medications.

What data supports the effectiveness of the drug combination of LHRH agonist, GnRH agonist, and Olaparib for prostate cancer?

Research shows that LHRH agonists are effective in treating hormone-sensitive prostate cancer by reducing testosterone levels, which can slow cancer growth. Additionally, Olaparib, a PARP inhibitor, has been effective in treating certain cancers by preventing cancer cells from repairing themselves, potentially enhancing the treatment's effectiveness when combined with hormone therapy. ^{1 2 3 4 5}

Is the combination of PARP inhibitors like Olaparib and hormone therapy safe for prostate cancer treatment?

Olaparib, a PARP inhibitor, has been studied for safety in combination with other treatments for prostate cancer and other cancers. Common side effects include fatigue and anemia (low red blood cell count), but it has been generally well-tolerated in clinical trials. Safety data from studies involving prostate cancer and other conditions suggest it can be safely combined with other therapies, though monitoring for side effects is important. ^{6 7 8 9 10}

How is the drug Olaparib with LHRH agonist unique for prostate cancer treatment?

This treatment combines Olaparib, a PARP inhibitor that targets cancer cell DNA repair, with an LHRH agonist, which reduces testosterone levels, offering a novel approach by attacking prostate cancer on two fronts, unlike traditional hormone therapies that primarily focus on hormone reduction alone. ^{3 4 5 11 12}

What is the purpose of this trial?

Phase 2 open-label, single-arm clinical trial evaluating the efficacy and safety of neoadjuvant olaparib + LHRH agonist administered for 6 months prior to radical prostatectomy (RP) in men with unfavorable intermediate-risk or high-risk localized prostate cancer. All patients must have confirmed germline or somatic select HRR alterations. Germline and somatic mutation testing will be performed as part of commercially available CLIA assays and will be validated on a uniform platform centrally all patients retrospectively. Eligible patients will receive treatment with olaparib + LHRH agonist. Following 6 months of therapy, patients will undergo RP with mandatory lymph node dissection. The lymph node dissection template will be at the discretion of the treating urologist. RP specimens will undergo pathology blinded independent central review. Following RP, patients will be followed for testosterone recovery and PSA progression.

Research Team

Rana R. McKay, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

Men over 18 with intermediate to high-risk localized prostate cancer and confirmed BRCA1/2 gene mutations, who are candidates for radical prostatectomy. They must not have had certain hormone therapies or chemotherapy for prostate cancer, no prior PARP inhibitors, and no severe health issues like heart disease or uncontrolled infections.

Inclusion Criteria

Written informed consent and HIPAA authorization for release of personal health information prior to registration

My prostate cancer is at an early to intermediate stage.

My scans show no cancer spread, and my lymph nodes are small.

Exclusion Criteria

Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL

I am currently on medication for an infection.

I have been treated with a PARP inhibitor before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant therapy with olaparib + LHRH agonist for 6 months

6 months

Monthly visits for 6 months

Surgery

Participants undergo radical prostatectomy with mandatory lymph node dissection

During surgery

Follow-up

Participants are monitored for testosterone recovery and PSA progression

4 years

Treatment Details

Interventions

• LHRH agonist
• Olaparib

Trial Overview The trial is testing the combination of olaparib (a PARP inhibitor) and an LHRH agonist given before surgery to remove the prostate in men with specific genetic changes linked to higher risk of aggressive cancer. The treatment lasts 6 months followed by surgery and evaluation of recovery.

Participant Groups

Group I: Investigational Group Experimental Treatment 2 Interventions

300 mg of olaparib taken orally twice a day for 6 cycles (approximately 6 months). There are 30 days in a cycle. Olaparib will be taken with an LHRH agonist (leuprolide, triptorelin, or goserlin). This choice of therapy will be taken for a total of 180 days per institutional standards. After 6 cycles of neoadjuvant therapy, patients will undergo a radical prostatectomy (RP). After RP, patients will be followed for testosterone recovery and PSA progression.

LHRH agonist is already approved in United States, European Union for the following indications:

Approved in United States as LHRH agonist for:

• Prostate cancer
• Endometriosis
• Uterine fibroids
• Precocious puberty

Approved in European Union as GnRH agonist for:

• Prostate cancer
• Endometriosis
• Uterine fibroids
• Precocious puberty

Who Is Running the Clinical Trial?

Rana McKay, MD

Lead Sponsor

Trials

2

Recruited

80+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

University of California, San Diego

Collaborator

Trials

1,215

Recruited

1,593,000+

Findings from Research

Apalutamide effectively blocks androgen receptor signaling in metastatic hormone-sensitive prostate cancer, leading to a rapid decrease in PSA levels and increased testosterone during monotherapy, indicating its efficacy in treatment.

Administering apalutamide 1 hour before GnRH agonists not only simplifies the treatment process but also effectively prevents testosterone flare-up, achieving castration levels of testosterone by day 28 without worsening side effects like dysuria or bone pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report. Hu, Z., Liu, Z., Chen, Z., et al.[2022]

In a study of 117 hormone-sensitive prostate cancer patients, those treated with GnRH antagonists showed a significantly higher prostate-specific antigen (PSA) control rate (54.28% without abiraterone and 88% with abiraterone) compared to those treated with GnRH agonists (47.91% without and 72% with abiraterone).

Propensity score matching revealed that the PSA control rates were 84.38% for antagonists versus 53.13% for agonists, indicating that GnRH antagonists are more effective in controlling PSA levels and serve as an independent predictor of treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of GnRH Antagonists and Agonists in Patients with Hormone-Sensitive Prostate Cancer: A Retrospective Study. Liu, Z., Yang, C., Zeng, X., et al.[2023]

GnRH antagonists provide faster suppression of hormones like luteinising hormone and testosterone compared to GnRH agonists, leading to improved disease control in advanced prostate cancer.

Patients receiving GnRH antagonists have a significantly lower risk of cardiac events within one year of treatment initiation, making them a safer option for men with pre-existing cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. Rosario, DJ., Davey, P., Green, J., et al.[2022]

In a study of 142 high-risk prostate cancer patients, six months of neoadjuvant therapy with LHRH agonist and low-dose estramustine phosphate (EMP) before radical prostatectomy resulted in a 4.9% rate of complete pathological response (pT0) and 87% of patients had negative surgical margins, indicating effective cancer control.

The treatment was well-tolerated with no serious adverse events reported, and at a median follow-up of 34.9 months, 84.3% of patients remained free of prostate-specific antigen (PSA) recurrence, suggesting promising efficacy and safety for this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study. Koie, T., Ohyama, C., Yamamoto, H., et al.[2013]

In a phase II study involving 62 advanced prostate cancer patients, high-dose estetrol (HDE4) combined with androgen deprivation therapy (ADT) significantly reduced the frequency and severity of hot flushes, with only 13.5% of patients experiencing weekly hot flushes compared to 60% in the placebo group.

HDE4 treatment also led to a more rapid and profound suppression of total and free testosterone, prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH), while showing no serious cardiovascular adverse events, indicating its potential for enhanced disease control and safety in ADT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer: A Randomized, Double-blind, Phase II Trial (PCombi). Coelingh Bennink, HJT., van Moorselaar, JA., Crawford, ED., et al.[2022]

Olaparib, a PARP inhibitor, has been approved for treating metastatic castration-resistant prostate cancer (mCRPC) in men with homologous recombination repair (HRR) gene mutations, which are present in about 27% of prostate cancer patients, showing improved overall survival in clinical trials.

The Phase III PROfound trial demonstrated that olaparib significantly benefits men with mCRPC who have progressed on other hormonal treatments, highlighting its role in targeted therapy based on genetic profiling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection. LeVee, A., Lin, CY., Posadas, E., et al.[2021]

In a phase I study involving 79 patients, the combination of the PARP inhibitor olaparib with endocrine therapies (tamoxifen, anastrozole, or letrozole) was found to be generally safe and well tolerated, with no significant pharmacokinetic interactions between the drugs.

While tamoxifen slightly decreased olaparib exposure, the overall safety profile remained acceptable, indicating that these combinations could be a viable treatment option for patients with advanced solid tumors, including breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Plummer, R., Verheul, HM., De Vos, FYFL., et al.[2019]

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]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib significantly improves progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC), with a hazard ratio of 0.59, indicating a 41% reduction in the risk of disease progression.

The addition of olaparib also shows a positive effect on overall survival (OS) with a hazard ratio of 0.81, although it is associated with a higher rate of adverse effects, necessitating further investigation into its safety and efficacy, especially in patients with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Olaparib to the New Hormonal Agent Regimen for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Warli, SM., Velaro, AJ., Firsty, NN., et al.[2023]

In a study of 406 high-risk prostate cancer patients, those treated with a neoadjuvant therapy of a gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate (GnRH + EMP) showed a significantly higher 2-year biochemical recurrence-free survival rate (97.8%) compared to those treated with luteinizing hormone-releasing hormone agonist plus low-dose estramustine (LHRH + EMP) (87.8%).

The rates of achieving pathological T0 status were similar between the two treatment groups (11.0% for GnRH and 8.9% for LHRH), indicating that while both treatments are effective, the GnRH + EMP regimen may offer better long-term outcomes in preventing recurrence after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: a single-center study. Hagiwara, K., Koie, T., Ohyama, C., et al.[2018]

In a study of 210 matched pairs of high-risk prostate cancer patients, those who received neoadjuvant therapy with LHRH agonist and estramustine phosphate (LHRH+EMP) before radical prostatectomy had a significantly higher 5-year biochemical recurrence-free survival rate of 90.4% compared to 65.8% for those who underwent surgery alone.

The overall survival rates were also high for both groups, with 100% for the LHRH+EMP group and 96.1% for the RP alone group, suggesting that while neoadjuvant therapy may improve recurrence rates, it does not negatively impact overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis. Koie, T., Mitsuzuka, K., Yoneyama, T., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report. [2022]

2. Egypt pubmed.ncbi.nlm.nih.gov

Effectiveness of GnRH Antagonists and Agonists in Patients with Hormone-Sensitive Prostate Cancer: A Retrospective Study. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer: A Randomized, Double-blind, Phase II Trial (PCombi). [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection. [2021]

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

Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. [2019]

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. England pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]

10. Canada pubmed.ncbi.nlm.nih.gov

Addition of Olaparib to the New Hormonal Agent Regimen for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. [2023]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy of a neoadjuvant gonadotropin-releasing hormone antagonist plus low-dose estramustine phosphate in high-risk prostate cancer: a single-center study. [2018]

12. Japan pubmed.ncbi.nlm.nih.gov

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis. [2018]