AZD5305 + Darolutamide for Prostate Cancer

(ASCERTAIN Trial)

Recruiting at 16 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: QT drugs, CYP3A4 drugs

Disqualifiers: Severe diseases, Cardiac issues, others

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

Compensation: Varies

Number of Visits: 1

Duration: 3-4 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

A Study to Investigate the Biological Effects of Saruparib (AZD5305) Alone, Darolutamide Alone, and in Combination Given Prior to Radical Prostatectomy in Men with Newly Diagnosed Prostate Cancer (ASCERTAIN).

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications or supplements that are strong CYP3A4 inducers/inhibitors or P-glycoprotein inducers at least 21 days before starting the study treatment. If you're taking any of these, you may need to stop or switch them.

What data supports the effectiveness of the drug combination AZD5305 + Darolutamide for prostate cancer?

Darolutamide, one of the drugs in the combination, has shown effectiveness in delaying metastasis (spread of cancer) and improving survival in men with nonmetastatic, castration-resistant prostate cancer. It works by blocking androgen receptors, which are involved in prostate cancer growth. ^{1 2 3 4 5}

Is the combination of AZD5305 and Darolutamide safe for humans?

Darolutamide has been shown to have a favorable safety profile in patients with prostate cancer, with a lower chance of side effects compared to similar drugs. It is considered safe for use in humans, but specific safety data for the combination with AZD5305 is not available. ^{2 5 6 7 8}

How is the drug AZD5305 + Darolutamide different from other prostate cancer treatments?

This treatment combines AZD5305, a novel drug, with darolutamide, a second-generation androgen receptor inhibitor that is effective in delaying metastasis in nonmetastatic, castration-resistant prostate cancer. Darolutamide is unique because it is structurally different from other androgen inhibitors and is taken orally, which may offer convenience compared to other treatment options. ^{3 5 6 9 10}

Eligibility Criteria

Men over 18 with newly diagnosed, localized prostate cancer suitable for surgery can join. They must have a biopsy sample available and be able to consent. Participants should not plan to father children and must use condoms during the study. Those with heart issues, severe diseases, or taking certain drugs affecting heart rhythm or immune system are excluded.

Inclusion Criteria

I am a man older than 18.

Participants must use a condom (with spermicide) from screening to 6 months after screening and refrain from fathering a child or donating sperm

My organs and bone marrow are working well.

Exclusion Criteria

I have heart or blood vessel problems, including recent heart attacks or strokes.

I do not have severe illnesses or infections like HepB, hepatitis C, or HIV.

I have a bleeding disorder or a history of blood cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Saruparib (AZD5305) alone, Darolutamide alone, or in combination for 21 days (+ up to 7 days) prior to radical prostatectomy

3-4 weeks

Daily administration

Surgery

Participants undergo radical prostatectomy following the treatment phase

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment and surgery

4 weeks

Treatment Details

Interventions

• No Treatment

Trial Overview The trial is testing AZD5305 alone, Darolutamide alone, and their combination in men before they undergo prostate removal surgery. The goal is to understand how these treatments affect prostate cancer at a biological level.

Participant Groups

Group I: Saruparib (AZD5305) only Experimental Treatment 1 Intervention

Participant will receive Saruparib (AZD5305) once daily for 21 days (+ up to 7 days) unless unacceptable toxicity or withdrawal of consent. Following the 21 days of study treatment, participants should undergo radical prostatectomy on Day 22 (+ up to 7 days)

Group II: Saruparib (AZD5305) + Darolutamide Experimental Treatment 2 Interventions

Participant will receive Saruparib (AZD5305) once daily + darolutamide twice daily for 21 days (+ up to 7 days) unless unacceptable toxicity or withdrawal of consent. Following the 21 days of study treatment, participants should undergo radical prostatectomy on Day 22 (+ up to 7 days).

Group III: No Treatment Experimental Treatment 1 Intervention

No study treatment is to be taken by the participants in this arm. Radical prostatectomy should be performed as per local practice

Group IV: Darolutamide Only Experimental Treatment 1 Intervention

Participant will receive darolutamide twice daily for 21 days (+ up to 7 days) unless unacceptable toxicity or withdrawal of consent. Following the 21 days of study treatment, participants should undergo radical prostatectomy on Day 22 (+ up to 7 days).

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

Findings from Research

Darolutamide, a novel nonsteroidal androgen receptor antagonist, has shown a favorable safety profile and significant antitumor activity in early trials for patients with metastatic castration-resistant prostate cancer (CRPC).

Ongoing phase III trials, such as ARAMIS and ARASENS, are evaluating darolutamide's effectiveness in improving metastasis-free survival and overall survival when combined with standard androgen deprivation therapy and docetaxel in men with high-risk nonmetastatic and metastatic hormone-sensitive prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. Fizazi, K., Smith, MR., Tombal, B.[2019]

In a study involving 249 men with metastatic castrate-resistant prostate cancer, patient preference between darolutamide and enzalutamide was balanced, with no significant preference for either treatment (p = 0.92).

Darolutamide was associated with less fatigue and a moderate improvement in episodic memory compared to enzalutamide, suggesting it may offer a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. Colomba, E., Jonas, SF., Eymard, JC., et al.[2023]

Darolutamide, an androgen receptor antagonist, significantly improves metastasis-free survival in men with non-metastatic, castration-resistant prostate cancer, based on a phase 3 trial involving 1509 participants.

The trial's findings suggest that darolutamide's effectiveness is comparable to other androgen inhibitors like apalutamide and enzalutamide, although its clinical relevance may be limited in the Netherlands due to the low incidence of non-metastatic cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Androgen receptor inhibitors in prostate cancer: new drugs, but for which patient?] Vis, AN., van Moorselaar, RJA.[2020]

In a phase 3 trial with 1306 patients suffering from metastatic, hormone-sensitive prostate cancer, the addition of darolutamide to standard treatment significantly reduced the risk of death by 32.5% compared to placebo, indicating its efficacy in improving overall survival.

The safety profile of darolutamide was comparable to placebo, with similar rates of adverse events, suggesting that it can be safely combined with androgen-deprivation therapy and docetaxel without increasing the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith, MR., Hussain, M., Saad, F., et al.[2023]

In a phase 3 trial involving 1509 men with nonmetastatic, castration-resistant prostate cancer, darolutamide significantly improved metastasis-free survival, with a median of 40.4 months compared to 18.4 months for placebo (hazard ratio 0.41).

The safety profile of darolutamide was comparable to placebo, with similar rates of adverse events and no increased risk of serious side effects like seizures or cognitive disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. Fizazi, K., Shore, N., Tammela, TL., et al.[2022]

Darolutamide, taken at 600 mg twice daily, shows predictable linear pharmacokinetics with a half-life of 13 hours, allowing for consistent inhibition of androgen receptor signaling in patients with nonmetastatic castration-resistant prostate cancer.

The absorption of darolutamide is significantly improved when taken with food, increasing its bioavailability from about 30% to 60-75%, which is important for optimizing treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment. Zurth, C., Nykänen, P., Wilkinson, G., et al.[2022]

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]

Darolutamide is a novel androgen receptor antagonist that has shown a high affinity for androgen receptors and maintains its effectiveness even against mutant forms, making it a promising option for treating nonmetastatic castration-resistant prostate cancer (nmCRPC).

Compared to other similar drugs like apalutamide and enzalutamide, darolutamide has a lower likelihood of causing adverse events, suggesting a better safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An up-to-date evaluation of darolutamide for the treatment of prostate cancer. Moussa, M., Lazarou, L., Dellis, A., et al.[2021]

In a phase III trial involving 95 Japanese patients with nonmetastatic castration-resistant prostate cancer, darolutamide significantly improved metastasis-free survival compared to placebo, with a hazard ratio of 0.28, indicating a strong reduction in the risk of metastasis.

Darolutamide was generally well tolerated, with treatment-emergent adverse events occurring in 85.5% of patients compared to 63.6% in the placebo group, although the small sample size limits definitive conclusions about safety differences in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial. Uemura, H., Matsushima, H., Kobayashi, K., et al.[2022]

Darolutamide, a new androgen receptor antagonist, was found to be well tolerated in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC), with most treatment-emergent adverse events being mild (Grade 1/2).

The pharmacokinetics of darolutamide showed a dose-dependent increase in drug levels, and while only 11% of patients showed a prostate-specific antigen response, the drug did not present any new safety concerns compared to Western populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. Matsubara, N., Mukai, H., Hosono, A., et al.[2023]

References

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

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. [2023]

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

[Androgen receptor inhibitors in prostate cancer: new drugs, but for which patient?] [2020]

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

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. [2023]

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

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment. [2022]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

An up-to-date evaluation of darolutamide for the treatment of prostate cancer. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. [2023]