PRIMARY OBJECTIVES:

I. To assess the difference in response rate (either achievement of prostate specific antigen [PSA] reduction of greater than 50% or radiographic response by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) of the combination of M6620 (ATR kinase inhibitor VX-970) and carboplatin as compared to the combination of docetaxel and carboplatin.

SECONDARY OBJECTIVES:

I. To assess the difference in time to PSA progression by Prostate Cancer Working Group (PCWG)2 criteria of the combination of M6620 and carboplatin as compared to the combination of docetaxel and carboplatin.

II. To describe radiographic progression-free survival and progression-free survival by PCWG3 criteria in both arms of the study.

III. Assess the relationship with homologous recombination deficiency (HRD) detected from baseline tumor biopsy with response to the combination of M6620 and carboplatin and the combination of docetaxel and carboplatin.

IV. To describe the safety and adverse events from the combination of M6620+carboplatin as well the combination of docetaxel+carboplatin.

EXPLORATORY OBJECTIVES:

I. Comparison of overall survival in the two arms of the study. II. Explore response rate, time to PSA progression, radiographic progression-free survival, and progression-free survival by PCWG3 criteria in patients who initially receive docetaxel+carboplatin after crossover to M6620+carboplatin.

III. To assess the relationship with homologous recombination deficiency (HRD) detected from baseline circulating free deoxyribonucleic acid (DNA) (cfDNA) with response to the combination of M6620 and carboplatin and the combination of docetaxel and carboplatin, and describe alterations seen in cfDNA (and optional tumor biopsy) at end of study.

OUTLINE: Participants are randomized to 1 of 2 groups.

ARM A (docetaxel, carboplatin): Participants receive docetaxel intravenously (IV) over 60 minutes and carboplatin IV over 30 minutes on day 1 or carboplatin alone on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Participants have PSA progression or radiographic progression may crossover to Arm B.

ARM B (carboplatin, ATR kinase inhibitor VX-970): Participants receive carboplatin IV over 30 minutes on day 1 and ATR kinase inhibitor VX-970 IV over 60 minutes on days 2 and 9. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up between 30-42 days.

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed prostate cancer
• Patients must have metastatic disease by bone scan or other nodal or visceral lesions on computed tomography (CT) or magnetic resonance imaging (MRI) and a castrate level of testosterone (< 50ng/dL) and evaluable for disease response by either
  • Baseline PSA ≥ 2.0 ng/mL OR
  • Measurable disease per RECIST 1.1
  • NOTE: Subjects must maintain a castrate state; if they have not had an orchiectomy, they must continue to receive luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists or antagonists unless intolerant
• At least 2 prior treatments for castration resistant prostate cancer as follows:
  • Past progression or intolerance to at least one secondary hormonal therapy (abiraterone, enzalutamide, galeterone, apalutamide, darolutamide, orteronel, seviteronel or equivalent)
  • Past progression or intolerance to taxane-based chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 × institutional upper limit of normal, unless the subject has known or suspected Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal or ≤ 5 x if presence of liver metastases
• Creatinine clearance ≥ 40 mL/min/1.73 m^2
• Prior treatment with mTOR inhibitors, cytostatic tyrosine kinase inhibitor (TKI), or biologic therapies allowed
• Prior treatment with PARP inhibitors permitted
• Patients with allergy or intolerance to docetaxel, grade 2 neuropathy or ECOG performance status (PS) = 2 are allowed on study, but if randomized to Arm A will receive carboplatin as a single agent (AUC 5) rather than docetaxel+carboplatin
• Willing to undergo core biopsy of a recurrent/metastatic lesion adequate for next generation sequencing prior to trial entry
• Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of carboplatin and M6620 administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), except for grade 2 anorexia, alopecia, neuropathy, and fatigue, for which resolution is not required
• Patients who are receiving any other investigational agents
• Patients with known brain metastases or leptomeningeal disease should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 or carboplatin; (patients with allergy to docetaxel will be allowed on study, but docetaxel will be excluded from their treatment regimen)
• Subjects receiving treatment with ototoxic or nephrotoxic medications that cannot be discontinued at least 7 days before first dose of carboplatin and for the duration of the study; inadvertent or short-term use on study will not cause a subject to be ineligible; if a short course of therapy with nephrotoxic or ototoxic medication is anticipated and required, carboplatin should be discontinued until 7 days after this course is completed
  • M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; (patient Drug Information Handout and Wallet Card) should be provided to patients; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and nursing women are excluded from this study
• Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
• Prior treatment with platinum-containing regimen or ATR inhibitor for prostate cancer