Talazoparib and Enzalutamide Receive FDA Approval for Advanced Prostate Cancer with HRR Gene Mutations

Recent cancer research findings offer new hope for metastatic castration-resistant prostate cancer (mCRPC), an area of intensive oncology research. The latest FDA approval represents an important step for the scientific community. This work advances understanding of mutation-based treatment approaches and helps pave the way for therapies selected according to cancer cells' genetic characteristics. 

FDA Approval for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer

On June 20, 2023, the FDA (US Food and Drug Administration) approved talazoparib (Talzenna, Pfizer) with enzalutamide for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

Talazoparib had previously been approved in 2018 for adults with deleterious or suspected deleterious germline (inherited) BRCA-mutated, HER2-negative, locally advanced or metastatic breast cancer.

TALAPRO-2, which tested talazoparib combined with enzalutamide, was one of the most notable presentations at the 2023 ASCO Genitourinary Cancers Symposium.

What Is an HRR Gene Mutation?

HRR stands for "homologous recombination repair." It describes a mechanism that cells use to repair damage when the DNA double helix breaks. During this process, broken DNA fragments are repaired using a homologous, or genetically similar, DNA segment as a template. This allows cells to copy genetic information accurately while maintaining genetic diversity and stability. 

An HRR gene mutation is a change in an HRR gene. HRR genes include ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 and RAD51C.

These genes normally repair cellular DNA and regulate cell division. Mutations can disrupt normal gene function, allowing cells to continue growing and dividing uncontrollably and potentially leading to cancer.

What Is Castration-Resistant Prostate Cancer?

Castration-resistant prostate cancer (CRPC) is prostate cancer that progresses despite treatments intended to lower testosterone levels, such as orchiectomy or androgen deprivation therapy. It generally arises when cancer cells continue growing and multiplying despite hormone therapy that was effective in the earlier stages of prostate cancer.

The term is often associated with metastatic disease, meaning cancer has spread to other organs. Metastatic castration-resistant prostate cancer (mCRPC) represents the most advanced stage of prostate cancer and often has limited treatment options. These patients frequently require complex treatment regimens and develop resistance to therapy. Finding and developing new treatments for mCRPC is therefore particularly important.

The Study Behind FDA Approval: TALAPRO-2

Efficacy was evaluated in the randomized, double-blind, placebo-controlled, multicohort TALAPRO-2 trial involving 399 patients with HRR gene-mutated mCRPC.

Patients were randomly assigned 1:1 to receive enzalutamide 160 mg once daily together with either talazoparib 0.5 mg or placebo.

Patients were required to have undergone orchiectomy or, if they had not, to be receiving gonadotropin-releasing hormone (GnRH) analogs.

Patients who had received prior systemic therapy for mCRPC were excluded. However, previous CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomization was stratified by prior CYP17 inhibitor or docetaxel treatment.

HRR genes were prospectively determined using next-generation sequencing assays based on tumor tissue and/or circulating tumor DNA (ctDNA).

Primary Efficacy Outcome and Statistical Significance

The primary efficacy outcome was radiographic progression-free survival (rPFS), describing how long treatment kept the disease under control.

• Median progression-free survival was 13.8 months in patients receiving enzalutamide plus placebo. However, more than half of those receiving talazoparib with enzalutamide were still responding favorably, so the median duration of disease control in this group could not yet be determined.
• The treatment-related risk level was particularly low in patients with BRCA-mutated prostate cancer (hazard ratio 0.20). Risk was somewhat higher among patients with mutations in other HRR genes (hazard ratio 0.72). These ratios are used to assess treatment effectiveness and patient response.

Adverse Effects

The most common adverse effects (10% or more), including laboratory abnormalities, were decreased hemoglobin, neutrophils and lymphocytes; fatigue; decreased platelets, calcium, appetite, sodium and phosphate; fractures; decreased magnesium; dizziness; increased bilirubin; decreased potassium; and dysgeusia.

Among all patients with mCRPC treated with talazoparib and enzalutamide in TALAPRO-2 (511 patients in total), 39% required blood transfusions, 22% of these patients needed more than one transfusion, and 2 patients were diagnosed with myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

Recommended Dosages

The recommended talazoparib dose is 0.5 mg orally once daily until disease progression or unacceptable toxicity. The recommended enzalutamide dose is 160 mg orally daily. Patients receiving talazoparib and enzalutamide should also receive a GnRH analog or have undergone bilateral orchiectomy.

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