AZD5305 + Darolutamide for Prostate Cancer

(ASCERTAIN Trial)

Recruiting at 14 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two drugs, Saruparib (AZD5305) and Darolutamide, both individually and in combination, for treating newly diagnosed prostate cancer. Participants will receive either one of the drugs, both drugs together, or no drug treatment before prostate surgery. The trial aims to assess how these treatments impact the cancer and prepare for surgery. Men with localized prostate cancer planning to undergo surgery might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive these potentially groundbreaking therapies.

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.

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

Research shows that Saruparib (AZD5305) is generally easy for patients to handle. In previous studies, it was safely used with other treatments and showed promising results for prostate cancer patients. Most side effects were mild and didn't last long.

Studies also suggest that Darolutamide is well-tolerated. Serious side effects were rare, and most people experienced only mild to moderate reactions. While some discomfort might occur, it's usually not severe.

Early research is examining the safety of using Saruparib and Darolutamide together. Initial evidence supports their combined use, but more information is still being collected.

Joining a clinical trial can involve some risks, but these drugs have shown promising safety records individually. Always consult a healthcare professional to understand what this means for your health. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the investigational treatments involving Saruparib (AZD5305) and Darolutamide for prostate cancer because they offer a fresh approach compared to standard hormone therapies and chemotherapy. Saruparib is a PARP inhibitor, which works by targeting and damaging cancer cell DNA, potentially enhancing the effectiveness of existing treatments. Combining Saruparib with Darolutamide, an androgen receptor inhibitor, could provide a dual-action strategy: attacking cancer cells' DNA and blocking the hormones that fuel prostate cancer growth. This innovative combination may offer a more rapid and potent response, aiming to improve outcomes for patients with prostate cancer.

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

Research has shown that Saruparib (AZD5305), one of the treatments in this trial, is a promising new option for prostate cancer. It targets and blocks PARP1, a protein that aids cancer cell repair, leading to increased cancer cell death. In studies with prostate cancer patients, 88.5% experienced tumor shrinkage, indicating the treatment's effectiveness. Darolutamide, another treatment option in this trial, has been proven to extend life in patients with certain types of prostate cancer. Participants may receive Saruparib alone, Darolutamide alone, or a combination of both. When used together, these treatments might more effectively halt cancer growth. This combination aims to leverage the strengths of both drugs to combat prostate cancer more successfully. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

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 can sign and understand the consent form.

Available FFPE diagnostic tumor biopsy samples

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

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.

Active HBV defined by a known positive HBsAg result; past or resolved HBV infection eligible

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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, 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 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]

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 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 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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e17108

Real world outcomes of darolutamide efficacy and safety in ... Adverse events led to dose reductions in 4.5% (n=6) of nmHSPC and 1.8% (n=1) of mHSPC patients. Surgical data for 51.1% (n=68) of nmHSPC ...

2. nature.com nature.com/articles/s41391-025-01047-7

DARolutamide ObservationaL (DAROL) study in patients ... Darolutamide showed consistent safety and effectiveness in DAROL vs ARAMIS. Most treatment-emergent adverse events were grade 1/2. Two-year ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40310703/

Real-world effectiveness of darolutamide in metastatic ... Darolutamide suppressed serum PSA levels by >50% in 5/44 M1-CRPC patients (11.4%), all previously 2GARA-naïve. M1-CRPC patients resistant only ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2119115

Darolutamide and Survival in Metastatic, Hormone ... Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration- ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.83

Efficacy outcomes 12 months after initiation of ... Conclusions: This RWE shows that patients with nmCRPC in clinical practice have comparable outcomes to the ARAMIS trial. Response rates, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37660438/

Efficacy and safety outcomes of darolutamide in patients ... Darolutamide significantly improved median metastasis-free survival by nearly 2 years and reduced the risk of death by 31% versus placebo, with a favourable ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38394384/

Extended Safety and Tolerability of Darolutamide for ... Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS.