A New Era in Prostate Cancer Treatment with Talazoparib and Enzalutamide

The combination of testosterone receptor inhibitor enzalutamide (Xtandi) and PARP inhibitor talazoparib (Talzenna) was tested in TALAPRO-2, which became the 2023 ASCO Genitourinary Cancers Symposium’s standout presentation. Patients receiving the combination had a lower risk of progression or death than those receiving standard treatment, enzalutamide alone, by 37%. The combination’s efficacy was observed in patients with and without HRR mutations.

Metastatic castration-resistant prostate cancer (mCRPC) means prostate cancer that has spread elsewhere after treatment has failed to control it. At this stage, the cancer keeps growing and spreading despite reduced testosterone levels achieved by therapies suppressing male hormones, or androgens. The disease is advanced and more difficult to treat.

Many Different Treatments Are Available for Advanced Prostate Cancer

There are now many first-line systemic options for prostate cancer that has spread to other organs and become resistant to conventional hormonal suppression. These include:

• New androgen receptor-directed drugs such as abiraterone and enzalutamide;
• Chemotherapies such as docetaxel and cabazitaxel;
• Spileucel-T, a personalized immunotherapy; and
• Molecular treatments such as radium-223 and lutetium-177.

Nevertheless, advanced prostate cancer currently has no prospect of complete cure, and the intensive search for more effective treatments continues.

Combinations of drugs introduced after 2010 may be described as a new era in prostate cancer treatment. One example, approved by the FDA for metastatic hormone-sensitive prostate cancer in August 2022, is darolutamide plus docetaxel. Although not yet FDA-approved, the TALAPRO-2 study discussed here demonstrated the efficacy of talazoparib plus enzalutamide for survival in mCRPC.

New Agents for Prostate Cancer: PARP Inhibitors

Approximately 20-40% of metastatic prostate cancer patients have HRR (homologous recombination repair) mutations (sometimes also called HDR). In cancer cells with these mutations, a mechanism needed to repair DNA is impaired. Drugs inhibiting PARP, another enzyme involved in repairing DNA damage, are therefore more effective at inhibiting the growth of HRR-mutant cancer cells. BRCA mutations are the most common mutations disrupting HRR.

In 2020, two PARP inhibitors, rucaparib and olaparib, received FDA (Food and Drug Administration of the United States) approval as single agents for metastatic castration-resistant prostate cancer (mCRPC). Talazoparib’s only FDA approval, however, was in 2018 for germline (inherited) BRCA mutation-positive advanced breast cancer.

The TALAPRO-2 Study

TALAPRO-2 is a phase III, multicenter, randomized, double-blind, placebo-controlled trial evaluating talazoparib plus enzalutamide versus placebo plus enzalutamide for radiographic progression-free survival in mCRPC.

The combination significantly reduced progression or death risk compared with placebo plus enzalutamide, by 37%. Benefit was observed in patients with and without HRR gene mutations.

The study involved more than 1000 mCRPC patients worldwide.

Baseline characteristics were well balanced. Median age was 71 in both arms, and median prostate-specific antigen (PSA) was 18.2 ng/mL with talazoparib and 16.2 ng/mL with placebo. Metastatic sites were bone (86.8% and 84.9%, respectively), lymph nodes (36.6% and 41.4%), lung (11.2% and 15.1%) and liver (3% and 4%).

Around 27 patients in each arm had previously received abiraterone or docetaxel. Approximately 79% in both arms had no HRR mutation or an unknown status.

Baseline HRR gene status was assessed in tumor tissue from 86.4% of the talazoparib arm and 86.1% of the placebo arm. Around 20% in both arms had one or more alterations in the corresponding HRR genes.

Following the presentation, sponsor Pfizer announced that the FDA had granted priority review to the supplemental application for talazoparib plus enzalutamide in mCRPC. Priority review is granted to applications offering a significant treatment advance or a new drug for a disease without adequate treatment. An approval decision is expected in 2023. sNDA stands for Supplement New Drug Application, an application supplementing an existing NDA. It can describe an important change or update, such as efficacy, safety or a new data indication. 

The most common side effects in the combination arm of TALAPRO-2 were anemia (65.8%), decreased neutrophils (35.7%), fatigue (33.7%), decreased platelets (24.6%), back pain, decreased white blood cells (22.1%) and decreased appetite (21.6%). Any-grade treatment-emergent adverse events occurred in 98.5% with talazoparib and 94.5% with placebo. Grade 3 to 4 treatment-related event rates were 71.9% and 40.6%, respectively. Grade 5 events occurred in 3.3% with talazoparib versus 4.5% with placebo.

A timeline of advanced prostate cancer treatment is shown below

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