Prostate - Advanced

Key Eligibility
1. Metastatic (conventional imaging; if only PET then bx required) prostate adenoca with an intact and resectable prostate.
2. Between 22 - 28 weeks of SST, without PD
3. No prior local therapy or other systemic therapy allowed
4. Oligometastatic disease may receive metastasis directed therapy to up to four sites
5. Visits every 3 months through 24 months, then every 6 months at M30, M36, until progression

Key Eligibility Criteria:

Inclusion Criteria:
1. Histologically/cytologically confirmed adenocarcinoma of prostate.
2. Metastatic disease by conventional imaging.
3. PSA of >/= 5.0 ng/ml (5.0 ug/L) prior to commencement of ADT.
4. Prior Therapy
a. Systemic Therapy
i. Receipt of ADT for mCSPC for at least 6 months and no greater than 12 months at time of enrollment.
ii. Receipt of ARPI (e.g. abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for at least 4 months at time of enrollment.
b. Radiotherapy
i. Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment.
5. Serum testosterone < 1.7 nmol/L or 50 ng/dL.
6. PSA >/= 0.2 ng/ml (0.2 ug/L) within 14 days of enrollment.
7. Candidate for docetaxel chemotherapy (per investigator).

Exclusion Criteria:
1. Two consecutive rises in PSA since achieving castration on ADT at least 2 weeks apart with at least one PSA >/= 5% above the PSA nadir and with at least one PSA having an absolute increase of >/= 0.5 ng/ml above the PSA nadir.
2. Evidence of radiographic progression or clinical progression since start of ADT.
3. High-grade neuroendocrine prostate cancer or small cell features.

Inclusion Criteria:
1. Participants must have histologically-confirmed (local site pathological confirmation sufficient) extrapulmonary poorly differentiated, neuroendocrine carcinoma (NEC).
2. Participants must have disease that is unresectable or metastatic and not eligible for definitive therapy as deemed per the treating investigator.
3. Participants with prior history of non-metastatic (localized/locally advanced disease) extrapulmonary poorly differentiated NEC may have had prior platinumbased therapy +/- radiation +/- surgery provided that all therapy was completed >/= 6 months prior to registration.
4. Participants must not have had prior treatment for advanced or metastatic NEC EXCEPT one cycle of platinum (carboplatin/cisplatin) + etoposide is allowed prior to registration. Other chemotherapy regimens are not allowed. For participants with prostate or urothelial NEC, prior chemotherapy for the non-NEC component (e.g. adenocarcinoma or urothelial) is allowed as long as such therapy was completed >/= 24 weeks prior to registration and participants have recovered from all prior toxicities to </= grade 1.
5. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, antiPD-L2, CD137 agonists, anti-CTLA-4 agent, or any other immune checkpoint inhibitors for any neuroendocrine neoplasm. Immune checkpoint inhibitors given for other cancer indications are allowed provided last therapy was given at least
12 months prior to study registration.

Key Eligibility Criteria:

Inclusion Criteria:
1. Histological or cytological evidence of prostate cancer. Patients with variant histologies including neuroendocrine, small cell and sarcomatoid prostate cancer are allowed to enroll and these will not be used as selection criteria for individual arms.
2. Tissue procured within 12 months of pre-registration (metastatic disease preferred over primary tissue, though both are acceptable) available for submission.
3. Molecular report available performed as part of standard of care testing. Patients may be assigned based on pre-determined qualifying molecular/DNA alterations after receipt of local molecular testing. Final determination of arm assignment will be determined by the MTB. If no qualifying DNA alteration is identified, Caris testing should be performed for both DNA/RNA profiling.
4. Progressive mCRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND one or more of the following criteria (choose all the apply):
5. PSA progression, defined by at least 2 consecutive rising PSA values at a minimum of 1-week intervals with the most recent PSA value being 2.0 ng/mL or higher, if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal of anti-androgen therapy.
6. Radiographic progression per RECIST 1.1 criteria for soft tissue lesions
7. Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3) criteria.
8. Prior treatment with ARSI in either the metastatic hormone sensitive setting or mCRPC is required. Prior taxane therapy in either metastatic hormone sensitive setting or mCRPC is mandated unless patient is taxane ineligible or the patient refuses taxane therapy. Prior lutetium LU177 vipivotide tetraxetan treatment is permitted but not mandated. Patients with known germline or somatic deleterious BRCA 1/2 mutations must have received a prior PARPi.
9. No prior treatment with EZH inhibitors.

Key Eligibility Criteria:
Inclusion Criteria:
1. Must have one of the following diagnoses under study:
a. RCC: Have histologically or cytologically confirmed advanced or metastatic RCC and have progressed on, are intolerant to, or have a contraindication to treatment with a VEGFR-TKI and an anti-PD-(L)1 antibody.
b. Urothelial carcinoma: Have histologically or cytologically confirmed advanced or metastatic urothelial carcinoma and have progressed on, are intolerant to, or have a contraindication to treatment with an anti-PD-(L)1 antibody and enfortumab vedotin-ejfv. Participants with susceptible FGFR3 or FGFR2 tumor genetic alterations must have progressed on, be intolerant to, or have a contraindication to treatment with an FGFR inhibitor, if approved and available in the study site's region.
c. Castration-resistant prostate cancer: Have a histologically or cytologically confirmed advanced or metastatic prostate cancer after treatment with at least 1 androgen receptor signaling inhibitor (such as abiraterone, enzalutamide, apalutamide, and darolutamide). Participants with prostate cancer must also fulfill both of the following:
i. Ongoing androgen deprivation from prior orchiectomy or continued luteinizing hormone-releasing hormone agonist or antagonist therapy with leuprolide, goserelin, buserelin, triptorelin, or degarelix and a Screening testosterone level of 50 ng/dL or less.
ii. At least 1 metastatic lesion outside the prostate and at least one of the following: any soft tissue lesion that is measurable according to RECIST v1.1 and/or a PSA level of at least 1 ng/mL.

Exclusion Criteria:
1. Has history of systemic arterial thrombotic or embolic events, such as cerebrovascular accident (including ischemic attacks) or moderate hemoptysis within 6 months prior to the first dose of study drug.
2. Has history of systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg, pulmonary embolism) unless they have been on stable anticoagulation for at least 30 days or the event has completely resolved and there is no need for ongoing treatment.


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Key Eligibility Criteria:

Inclusion Criteria:
1. Pathologically confirmed adenocarcinoma of the prostate.
2. Diagnosis of mCRPC.
3. Documented progression on androgen deprivation and novel hormonal agents, with or without progression on taxane containing regimen.
4. Ongoing ADT to maintain serum testosterone levels below 50 ng/dL.
5. Formalin fixed paraffin embedded tumor tissue for HER2 immunohistochemistry.

Exclusion Criteria:
1. History of interstitial lung disease or pneumonitis requiring steroids
2. Significant coronary vascular disease
3. Previous exposure to HER2 targeted therapy

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Key Eligibility Criteria:
Inclusion Criteria:
1. Participants must have histological, and/or cytological confirmation of prostate adenocarcinoma.
2. Participants with safely accessible tumor lesion must agree to biopsy of a primary or metastatic lesion during screening. They may provide an archival biopsy of a primary or metastatic lesion that was taken after castration resistance developed and within 1 year prior to randomization.
3. Participants must have serum testosterone levels <50 ng/dL during screening.
4. Participants are required to have progressed on one prior treatment with a second-generation ARSI initiated in either the castration-sensitive or castration-resistant setting.
5. Participant must have progressive mCRPC following last treatment at screening.

Exclusion Criteria:
1. Participant has received previous treatment with a therapeutic targeting CD46.
2. Participant has small cell neuroendocrine carcinoma (pure or mixed) or any other non-adenocarcinoma component on prior or current histologic evaluation of primary or metastatic lesion.
3. Participant has received more than one prior second-generation ARSI in any setting.
4. Participant has a known actionable mutation or gene alteration.

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Key Eligibility Criteria:

Inclusion Criteria:
1. Has prostate cancer progression while on ADT (or post bilateral orchiectomy) within 6 months prior to Screening, as determined by the investigator, by means of one or more of the following:
a) Clinical disease progression and with PSA progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of >/=1 week between each assessment where the PSA value at Screening should be >/=1 ng/mL.
b) Radiographic disease progression in soft tissue based on RECIST 1.1 criteria.
c) Radiographic disease progression in bone based on PCWG3, defined as the appearance of 2 or more new bone lesions on bone scan.
2. Has progression under the following conditions if the participant received first generation antiandrogen therapy prior to enrollment:
a) Evidence of progression >4 weeks since last flutamide treatment.
b) Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment.
3. Has received prior treatment with 1 or 2 ARPI(s) for nmHSPC, mHSPC, nmCRPC, or mCRPC and progressed during or after at least 8 weeks of treatment.
4. Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM). If the participant is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists, this therapy must have
been initiated at least 4 weeks prior to randomization and treatment must be continued throughout the study.
5. Has had prior treatment with PARPi if indicated by local approved regimen or were deemed ineligible to receive treatment by the investigator.

Exclusion Criteria:
1. Clinically significant corneal disease.
2. All of the following indicators of ILD/pneumonitis are excluded:
a) Any history of ILD/pneumonitis irrespective of steroid use, except for a history of radiation pneumonitis that did not require steroids
b) Current diagnosis of ILD
c) Clinical or radiographic suspicion of ILD for which the diagnosis of ILD cannot be ruled out.
3. Has received prior treatment with a taxane-based chemotherapy agent for mCRPC
4. Prior treatment with orlotamab, enoblituzumab, or other B7-H3-targeted agents, including I-DXd.
5. Prior discontinuation of an ADC that consists of an exatecan derivative due to treatment-related toxicities.

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