New drug combo shows promise for Hard-to-Treat prostate cancer

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: * History of histologically diagnosed prostatic adenocarcinoma * Participants must have progressed on no more than one novel hormonal therapy (NHT) by PSA or radiographic criteria (per Prostate Cancer Working Group 3 \[PCWG3\] or Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1) and a castrate serum testosterone level (i.e., ≤ 50 ng/dL). If progressive disease by radiographic criteria, PSA must be ≥ 2ng/ml. PSA progression will be defined as at least two successive PSA rises above the nadir, separated by ≥ 1 week, with the last determination having a value of ≥ 2 ng/mL. NHTs include but are not limited to either abiraterone, enzalutamide, darolutamide, or apalutamide. (Biosimilar or generic agents may be allowed at the discretion of the principal investigator \[PI\].) Note: prior NHT exposure that did not result in disease progression will not be counted as prior line, i.e., patient's that completed prior abiraterone course in the localized setting, patients that changed NHT due to toxicity or financial toxicity * Participants must have previously progressed on a novel hormonal therapy (NHT) by PSA or radiographic criteria (per PCWG3 or RECIST v1.1). NHTs include but are not limited to either abiraterone, enzalutamide, darolutamide, or apalutamide. (Biosimilar or generic agents may be allowed at the discretion of the principal investigator \[PI\].) Note: prior NHT exposure that did not result in disease progression will not be counted as prior line, i.e., patient's that completed prior abiraterone course in the localized setting, patients that changed NHT due to toxicity or financial toxicity * Participants may have received one prior line of taxane chemotherapy in any setting * Participants must be \>= 18 years of age prior to signing informed consent * Eastern Cooperative Oncology Group (ECOG) performance status score =\< 2 * Hemoglobin \>= 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization * Platelet count \>= 100,000 x 10\^9/uL independent of transfusion and/or growth factors within 3 months prior to randomization * Absolute neutrophil count \>= 1.5 x 10\^3/mL * Serum albumin \>= 3.0 g/dL * Serum creatinine =\< 1.5 mg/dL * Serum potassium \>= 3.5 mmol/L * Serum total bilirubin \< 1.5 x upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is \> 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =\< 1.5 x ULN, subject may be eligible) * Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase =\< 1.5 x ULN * Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug * Medications known to lower the seizure threshold (see list under prohibited meds) must be discontinued or substituted at least 4 weeks prior to study entry * Have had no known recent close contact with a person with active tuberculosis (TB) or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation * Participants must sign an informed consent form (ICF) indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study Exclusion Criteria: * Subjects may not be receiving other investigational agents within 14 days prior to enrollment * Subjects with predominant small cell or neuroendocrine variant prostate cancer on most recent standard of care biopsy * Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition that could interfere with patient safety * Symptomatic central nervous system (CNS) metastases. Treated CNS metastases will be allowed if these are stable for at least 8 weeks prior to enrollment * Uncontrolled or active infection, including: * Hepatitis B infection (acute or chronic) as defined according to the American Society of Clinical Oncology guidelines, or hepatitis C infection (anti-hepatitis C virus \[HCV\] antibody positive and HCV-ribonucleic acid \[RNA\] quantitation positive) * Recent serious infection (e.g., requiring IV antibiotics or hospitalization within last two months) * Herpes zoster infection within 2 months of screening * History of active granulomatous infection, including histoplasmosis, or coccidioidomycosis * HIV (HIV antibody positive) * Active or untreated latent tuberculosis * History of infected joint prosthesis or received antibiotics for suspected infection of a joint prosthesis in the past five years, if that prosthesis has not been removed or replaced * Less serious infections (e.g., acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator * Has impaired wound healing capacity defined as current skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions * Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration (Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate) * Co-administration of other TNF-alpha inhibitors or disease-modifying anti-rheumatic drugs (DMARDS) for the treatment of rheumatoid arthritis or other rheumatologic condition. (Note: prior exposure to TNF-alpha inhibitors is allowed for non-rheumatologic disease (e.g., SARS-CoV-2) if washout period \> 5 half-lives prior to study enrollment) * Any other issue that would impair the ability of the subject to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments * Presence of significant cardiovascular disease including New York Heart Association (NYHA) class II-IV heart failure, uncontrolled arrhythmia, myocardial infarction (MI) or stroke within 6 months * History of autoimmune disorder, including multiple sclerosis or optic neuritis, lupus or lupus-like Syndrome * Hypersensitivity to any biologics or known allergies or clinically significant reactions to murine, chimeric, or human proteins, monoclonal antibodies (mAbs), or antibody fragments * Have a transplanted organ (with the exception of a corneal transplant performed \> 3 months prior to first administration of study drug) * Currently has a malignancy or a history of malignancy within 3 years before screening (with the exception of prostate cancer, treated superficial bladder cancer, or a nonmelanoma skin cancer that has been adequately treated with no evidence of recurrence for at least 3 months prior to the administration of the first study intervention * Immune deficiency syndrome (e.g., severe combined immunodeficiency syndrome \[SCIDS\], T cell deficiency syndromes, B cell deficiency syndromes, and chronic granulomatous disease) * Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of screening. Patients must agree not to receive BCG vaccination during the study and within 16 weeks after the last administration of study intervention * Known allergies, hypersensitivity, or intolerance to apalutamide or its excipients * Gastrointestinal disorder affecting absorption * History of seizure or any condition that in the opinion of the investigator may predispose to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks prior to starting treatment with apalutamide