This study will test whether BNT324 is safe and works better against metastatic castration-resistant prostate cancer (mCRPC) than the current standard of care (SoC) chemotherapy, which is docetaxel (given together with the steroid medicines prednisone or prednisolone). The study will include participants with mCRPC that have been previously treated with androgen receptor pathway inhibitor, but with no previous taxane-based systematic chemotherapy for mCRPC.

The main goals of this study are:

• To find out if BNT324 helps participants live longer without their cancer getting worse (radiographic progression-free survival [rPFS]).
• To find out if BNT324 helps participants live longer overall (overall survival [OS]).

The study consists of a screening period (up to 28 days), a treatment period with 21-day cycles, and an after-treatment period that includes a 30-day safety follow-up period and a long-term survival follow-up period.

Treatment continues until the cancer clearly gets worse (in scans, based on blinded independent central review [BICR] assessment or investigator's decision), side effects become unacceptable, the participant chooses to stop, or the study ends.

Participants are put into one of two groups in a 1:1 ratio, which means they will have an equal chance to be in either treatment group, i.e., BNT324 group, or docetaxel plus prednisone/prednisolone group (current SoC). An independent committee will help ensure participant safety, by regularly reviewing safety and early results.

For each participant, the treatment and follow-up periods are projected to be up to ~58 months.

Key Inclusion Criteria:

• Are male adults (defined as ≥18 years of age or of an acceptable age according to local regulations at the time of giving informed consent).

• Must have documented progressive prostate cancer based on at least one of the following criteria:

  • Serum/plasma PSA progression, by local laboratory, defined as two consecutive increases in PSA over a previous reference value, each measured sequentially at least 1 week apart. The PSA value at screening is required to be ≥1.0 ng/mL.
  • Radiographic soft tissue progression as per PCWG3-modified RECIST v1.1.
  • Radiographic progression of bone disease: evaluable disease or new bone lesion(s) by bone scan per PCWG3 criteria.

• Had previously received one or two prior androgen receptor pathway inhibitor treatments and experienced disease progression during or after a minimum of 8 weeks of therapy.

• Must not have received systemic cytotoxic chemotherapy, including taxane-based chemotherapy, for mCRPC.

• Must have had prior orchiectomy and/or have ongoing androgen-deprivation therapy and a castrate-level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L). Participant being treated with luteinizing hormone-releasing hormone agonists or antagonists must continue such treatment throughout the study.

• Must have an Eastern Cooperative Oncology Group performance score of 0 or 1.

Key Exclusion Criteria:

• Have received prior treatment with B7-H3 targeted therapy, including B7-H3 ADCs.
• Have uncontrolled or significant cardiovascular disease, as defined in the protocol.
• Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids or have current ILD/pneumonitis.

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.