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A Phase 1, Multicenter Trial Evaluating the Safety, Tolerability, and Efficacy of Valemetostat (DS-3201) in Combination with Darolutamide in Metastatic Castration Resistant Prostate Cancer (mCRPC)

A Study of Valemetostat (DS-3201b) in Combination with Darolutamide in Metastatic Castration Resistant Prostate Cancer (mCRPC)

Inoguchi Akihiro

Daiichi Sankyo Co., Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial_jp@daiichisankyo.com

Contact for Clinical Trial Information

Daiichi Sankyo Co., Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial_jp@daiichisankyo.com

Recruiting

Jan. 01, 2026

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

The clinical site will screen for the full inclusion criteria per protocol.
1. Adult males >=18 years of age at the time the ICF is signed (Please follow local regulatory requirements if the legal age of consent for trial participation is >18 years old).
2. Histologically confirmed adenocarcinoma of the prostate. Cases exhibiting neuroendocrine differentiation are eligible for enrollment, except those with a diagnosis of pure small cell carcinoma, which is excluded.
3. Evidence of disease progression as per the PCWG3 modified RECIST v1.1 criteria.
4. Evidence of metastatic disease as confirmed by radiographic imaging (CT, MRI, or bone scan).
5. Ongoing androgen deprivation at time of enrollment.
- For participants currently being treated with luteinizing hormone-releasing hormone agonists or antagonists, therapy must have been initiated at least 4 weeks prior to enrollment and treatment must be continued throughout the trial.
6. Baseline PSA expression level of >=2 ng/mL, according to a documented testing result.
7. Prior therapy with an Androgen Receptor Pathway Inhibitors (ARPI).
8. ECOG PS of 0 or 1 assessed no more than 28 days prior to enrollment.
9. Is willing and able to provide adequate fresh or archival tumor samples with sufficient quantity and tissue quality. A mandatory newly obtained pretreatment biopsy is required, if not clinically contraindicated and at an acceptable risk as determined by the investigator. If newly obtained tissue samples are not possible to obtain, archival tissue obtained from a lesion not previously irradiated and collected after the most recent prior therapy is acceptable.
10. A male participant capable of producing sperm is eligible to participate if he agrees to the following during the intervention period and for at least the time needed to eliminate each trial intervention. The length of time required to continue contraception after the last dose for each trial intervention is 3 months.
- Must not freeze or donate sperm starting at screening and throughout the Treatment Period, and for at least 3 months after the final trial intervention administration.
Note: Preservation of sperm should be considered before enrollment in this trial.
- Adhere to either of the following contraception methods:
- True abstinence from penile-vaginal intercourse, when this is in line with the preferred and usual lifestyle of the participant,
OR
- Uses a penile/external condom when having penile-vaginal intercourse with an NPOCBP, PLUS partner use of an additional contraceptive method, as a condom may break or leak
Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. If the contraception requirements in the local label for any trial interventions are more stringent than those above, the local label requirements are to be followed.

The clinical site will screen for the full exclusion criteria per protocol.
1. Prior treatment with any epigenetic agents including but not limited to EZH1, EZH2, EZH1/2, or PRC2 inhibitors.
2. Has a super scan as seen in the baseline bone scan. A super scan is defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan, such that the presence of additional metastases in the future could not be evaluated.
3. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.
4. Uncontrolled or significant cardiovascular disease.
5. Prior malignancy, active within the previous 3 years except for locally curable cancers that have been apparently cured or successfully resected, such as basal or squamous cell carcinoma, superficial bladder cancer, carcinoma in situ of the stomach, or carcinoma in situ of the breast.
6. Has active or uncontrolled HBV infection.
7. Has active or uncontrolled HCV infection.
8. Has active or uncontrolled HIV infection.

Male

Metastatic castration-resistant prostate cancer

Experimental: Part 1 (Dose Escalation)
Participants will receive valemetostat at escalating doses in combination with darolutamide.
Drug:
Valemetostat
Valemetostat will be administered at escalating doses.
Darolutamide
Darolutamide will be administered at a standard dose.

Experimental: Part 2 (Dose Expansion)
Participants will receive valemetostat at 2 or more dose levels in combination with darolutamide.
Drug:
Valemetostat
Valemetostat will be administered at 2 or more dose levels.
Darolutamide
Darolutamide will be administered at a standard dose.

Part 1: Number of participants with Dose-Limiting Toxicities (DLTs)
A DLT is defined as any Treatment Emergent Adverse Event (TEAE) not attributable to disease or disease-related processes, environmental factors, unrelated trauma, etc, that occurs during the DLT evaluation period (Day 1 to Day 28) and is Grade >=3.
[Time Frame: Day 1 up to Day 28]

Part 1 and 2: Number of Participants Experiencing a Treatment Emergent Adverse Event (TEAE)
TEAEs are defined as those Adverse Events (AEs) with start or worsening date during the on-treatment period (from the first dose date of trial intervention to 30 days after the last dose date of trial intervention).
[Time Frame: From Screening up to approximately 5 years]

Prostate-Specific Antigen (PSA) 50 Response Rate
PSA50 response rate is defined as the percentage of participants who achieved a decline in PSA percent change from baseline by at least 50%, with a consecutive confirmation assessment at least 3 weeks later per the PCWG3 modified RECIST v1.1 criteria.
[Time Frame: From Screening up to approximately 5 years]

Prostate-Specific Antigen (PSA) 90 Response Rate
PSA90 response rate is defined as the percentage of participants who achieved a decline in PSA percent change from baseline by at least 90%, with a consecutive confirmation assessment at least 3 weeks later per the PCWG3 modified RECIST v1.1 criteria.
[Time Frame: From Screening up to approximately 5 years]

Prostate-Specific Antigen (PSA) Nadir Response Rate
PSA nadir response rate is defined as the proportion of participants who achieve a PSA level of <= 0.2 ng/mL at any time during the Treatment Period.
[Time Frame: From Screening up to approximately 5 years]

Radiographic Progression-Free Survival (rPFS)
rPFS is defined as the time (month) from the start date of trial intervention to the earlier date of the first objective documentation of radiographic disease progression as assessed by the investigator based on the PCWG3 modified RECIST v1.1 criteria or death due to any cause.
[Time Frame: From Screening up to approximately 5 years]

Overall Survival (OS)
OS is defined as the time (month) from the start date of trial intervention to the date of death due to any cause.
[Time Frame: From Screening up to approximately 5 years]

Time to PSA Progression
Time to PSA progression is defined as the time interval from the start date of trial intervention to PSA progression, per the PCWG3 modified RECIST v1.1 criteria. PSA progression is defined as:
- A >=25% increase and an absolute increase of >=2 ng/mL from the nadir, confirmed by a second PSA measurement obtained at least 3 weeks later, in participants who experience a decline in PSA from baseline;
OR
- A >=25% increase and an absolute increase of >=2 ng/mL from baseline, occurring beyond 12 weeks from treatment initiation, in participants who do not experience a PSA decline from baseline.
[Time Frame: From Screening up to approximately 5 years]

Objective Response Rate (ORR)
ORR is defined as the proportion of participants with measurable disease who achieved a BOR of confirmed CR or confirmed PR as assessed by the investigator according to the PCWG3 modified RECIST v1.1 criteria.
[Time Frame: From Screening up to approximately 5 years]

Time to First SSRE (symptomatic bone fractures, spinal cord compression, surgery, or radiation to the bone, whichever is first)
Time to first SSRE (symptomatic bone fractures, spinal cord compression, surgery, or radiation to the bone, whichever is first) is defined as the time interval from the start date of trial intervention to the date of the first observed SSRE.
[Time Frame: From Screening up to approximately 5 years]

Total and Unbound Plasma Concentration of Valemetostat in Combination with Darolutamide
[Time Frame: Cycle 1: Day 1, Day 8, Day 15. Cycles 2-5: Day 1 (Each cycle is 28 days)]

+81-3-3520-0111

Nov. 05, 2025

Yes

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