TALAPRO-3 Clinical Trial Protocol: Phase III Study of Talazoparib Plus Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer

Figures & data

Figure 1. Mechanistic overview of PARP inhibition.

(A) Dual cytotoxic mechanisms of PARP inhibitors; (B) PARP inhibitor in combination with an ARSI.

Adapted with permission from Future Oncology [29]. Reprinted (or adapted) from Cancer Research [30].

AR: Androgen receptor; ARSI: Androgen-receptor signaling inhibitor; DDR: DNA damage response; DSB: Double-strand break; HRD: Homologous recombination deficiency; PARP: Poly(ADP-ribose) polymerase; PARPi: Poly(ADP-ribose) polymerase inhibitor; SSB: Single-strand break.

Figure 2. An overview of the talazoparib prostate cancer program.

*No prior life-prolonging systemic therapy for castration-sensitive prostate cancer, excluding ≤3 months androgen deprivation therapy with or without an approved androgen-receptor signaling inhibitor; treatment with estrogens, cyproterone acetate, or first-generation anti-androgens is allowed until randomization.

^†No prior life-prolonging systemic therapy for castration-resistant prostate cancer, excluding androgen deprivation therapy and first-generation antiandrogens.

mCRPC: Metastatic castration-resistant prostate cancer; mCSPC: Metastatic castration-sensitive prostate cancer; nmCRPC: Non-metastatic castration-resistant prostate cancer.

Figure 3. Study design.

mCSPC: Metastatic castration-sensitive prostate cancer; PO: Per oral.

Figure 4. TALAPRO-3 enrollment.

Table 1. Key inclusion and exclusion criteria of the TALAPRO-3 study.

Key inclusion criteria
Demographics	• Male, aged ≥18 years at screening ^†
Additional criteria	• ECOG performance status ≤1 • Willing to provide tumor tissue when available (de novo or archived) for retrospective molecular profiling analysis and consent to provide saliva for retrospective sequencing of the same HRR genes tested on tumor tissue and blood and to serve as a germline control in identifying tumor mutations • Adequate organ function within 28 days before the first study treatment on day 1, defined by the following:   ○ ANC ≥1500/μl, platelets ≥100,000/μl, or hemoglobin ≥9 g/dl (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology laboratory tests at screening)   ○ Total serum bilirubin <1.5 × ULN (<3 × ULN for patients with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation)   ○ AST or ALT <2.5 × ULN (<5 × ULN if liver function abnormalities are due to hepatic metastasis)   ○ Albumin >2.8 g/dl   ○ eGFR ≥30 ml/min/1.73 m^2 by the MDRD equation • Signed informed consent
Prostate cancer status	• Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, small-cell or signet cell features • Ongoing ADT with a GnRH agonist/antagonist for patients who have not undergone bilateral orchiectomy; ADT must be initiated before randomization and must continue throughout the study • Metastatic prostate cancer documented by positive bone scan (for bone disease) or by CT or MRI scan (for soft tissue disease) • Confirmation of HRR gene mutation status (per HRR12 panel) by prospective or historical analysis of blood (FoundationOne Liquid CDx) and/or de novo or archival tumor tissue (FoundationOne CDx) • Palliative radiation or surgery for symptomatic control secondary to prostate cancer should be completed ≥2 weeks prior to randomization
Concomitant medication	• Treatment with estrogens, cyproterone acetate, or first-generation anti-androgens is allowed until randomization • Other prior therapy allowed for mCSPC: ≤3 months of ADT (chemical or surgical) with or without an approved ARSI ^‡ in mCSPC (i.e., abiraterone plus prednisone, apalutamide, or enzalutamide), if required prior to randomization, with no radiographic evidence of disease progression or rising PSA levels prior to day 1
Key exclusion criteria
Medical conditions	• History of seizure or any condition (as assessed by investigator) that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma), including any history of loss of consciousness or transient ischemic attack within 12 months of randomization • Major surgery within 4 weeks before randomization • Any history of MDS, AML, or prior malignancy except for the following:   ○ Carcinoma in situ or non-melanoma skin cancer   ○ A cancer diagnosed and treated ≥3 years before randomization with no subsequent evidence of recurrence • AJCC Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence in the opinion of the investigator and the sponsor • Clinically significant cardiovascular disease, including any of the following:   ○ Myocardial infarction or symptomatic cardiac ischemia within 6 months before randomization   ○ Congestive heart failure New York Heart Association class III or IV   ○ History of clinically significant ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening   ○ History of Mobitz II second-degree or third-degree heart block unless a permanent pacemaker is in place   ○ Hypotension as indicated by systolic blood pressure <86 mm Hg at screening   ○ Bradycardia as indicated by a heart rate of <45 beats per minute on the screening electrocardiogram • Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening
Prior/concomitant therapy	• Prior ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was ≤12 months prior to randomization and the total duration of ADT >36 months • Treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to randomization, intended for the treatment of prostate cancer • Any previous treatment with DNA-damaging cytotoxic chemotherapy (i.e., platinum-based therapy) within 5 years prior to randomization, except for indications other than prostate cancer • Prior treatment with a PARPi or known or possible hypersensitivity to enzalutamide, any of enzalutamide capsule excipients or any talazoparib/placebo capsule excipients • Prior treatment in any setting with any ARSI, except as described in the inclusion criteria • Prior or concurrent docetaxel • Current use of potent P-gp inhibitors within 7 days prior to randomization • Treatment with any investigational study intervention within 4 weeks before randomization; COVID-19 vaccines are an exception and can be administered without a washout period

† ≥20 years in Japan; ≥19 years in the Republic of Korea.

‡ Darolutamide is not included as it was not an approved androgen-receptor signaling inhibitor at the study entry.

ADT: Androgen deprivation therapy; ARSI: Androgen-receptor signaling inhibitor; AJCC: American Joint Committee on Cancer; ALT: Alanine aminotransferase; AML: Acute myeloid leukemia; ANC: Absolute neutrophil count; AST: Aspartate transferase; ECOG: Eastern Cooperative Oncology Group; eGFR: Estimated glomerular filtration rate; GnRH: Gonadotropin-releasing hormone; HRR: Homologous recombination repair; mCSPC: Metastatic castration-sensitive prostate cancer; MDRD: Modification of diet in renal disease; MDS: Myelodysplastic syndrome; PARPi: Poly(ADP-ribose) polymerase inhibitor; P-gp: P-glycoprotein; PSA: Prostate-specific antigen; ULN: Upper limit of normal.

Table 2. TALAPRO-3 study end points.

Primary end point

Secondary end points

• rPFS based on investigator assessment per RECIST 1.1 (soft-tissue disease) and PCWG3 (bone disease)   ○ rPFS is defined as time from randomization to first evidence of radiographic progression by investigator, or death, whichever occurs first   ○ Efficacy will be assessed by radiography every 8 weeks through week 57, and every 12 weeks thereafter   ○ rPFS will be compared between the two arms by a two-sided stratified log-rank test

• OS, defined as the duration from the date of randomization until the date of death from any cause • Objective response (in participants with measurable soft-tissue disease) ^† • Duration of soft-tissue response ^† • Time to first symptomatic skeletal event (spinal cord compression, symptomatic pathologic bone fracture, or radiation or surgery to bone) • Proportion of patients with PSA response ≥50% • Time to PSA progression • Time to initiation of antineoplastic therapy • Time to opioid use for prostate cancer pain • Incidence and severity of AEs (graded by NCI CTCAE version 4.03) • PK of talazoparib, enzalutamide, and its N-desmethyl metabolite • ctDNA burden at baseline and on study Patient-reported outcomes: • Change from baseline in PGI-S, participant-reported pain symptoms (BPI-SF), general health status (EQ-5D-5L), cancer-specific global health status/QoL, functioning, and symptoms (EORTC QLQ-C30) • Time to deterioration in BPI-SF, global health status/QoL (EORTC QLQ-C30), and disease-specific urinary symptoms (EORTC QLQ-PR25)

† Per RECIST 1.1.

AE: Adverse event; BPI-SF: Brief Pain Inventory Short Form; CTCAE: Common Terminology Criteria for Adverse Events; ctDNA: Circulating tumor DNA; EORTC: European Organisation for Research and Treatment of Cancer; EQ-5D-5L: European quality of life 5D, 5-level scale; NCI: National Cancer Institute; OS: Overall survival; PCWG3: Prostate Cancer Working Group 3; PGI-S: Patient Global Impression of Severity; PK: Pharmacokinetics; PSA: Prostate-specific antigen; QLQ-C30: Quality of Life Questionnaire C30; QLQ-PR25: Quality of Life Questionnaire Prostate Cancer Module PR25; QoL: Quality of life; RECIST 1.1: Response Evaluation Criteria in Solid Tumors version 1.1; rPFS: Radiographic progression-free survival.

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Data sharing statement

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.