On February 13, 2025 Pfizer Inc. (NYSE: PFE) reported positive results from the Phase 3 TALAPRO-2 study of TALZENNA (talazoparib), an oral poly ADP-ribose polymerase (PARP) inhibitor, in combination with XTANDI (enzalutamide), an androgen receptor pathway inhibitor (ARPI), demonstrating a statistically significant and clinically meaningful improvement in overall survival (OS) compared to placebo plus XTANDI in patients with metastatic castration-resistant prostate cancer (mCRPC), with or without homologous recombination repair (HRR) gene mutations (Press release, Seagen, FEB 13, 2025, View Source [SID1234650264]). The TALAPRO-2 results will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium in San Francisco and featured in the ASCO (Free ASCO Whitepaper) GU official Press Program.
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The TALAPRO-2 study evaluated two sets of patients, unselected (cohort 1) and selected for HRR gene-mutations (cohort 2). Overall survival was a prespecified, alpha-protected key secondary endpoint. After more than four years of median follow-up (52.5 months), the median OS in cohort 1 was 45.8 months with TALZENNA in combination with XTANDI, and 37.0 months with XTANDI and placebo (Hazard Ratio [HR] of 0.80; 95% Confidence Interval [CI], 0.66-0.96; p=0.015), representing a 20% reduction in the risk of death. This represents a nearly 9-month gain in median OS versus standard of care XTANDI. Data from cohort 1 will be presented today at ASCO (Free ASCO Whitepaper) GU in an oral presentation (Abstract LBA18) by Dr. Neeraj Agarwal, global lead investigator for TALAPRO-2.
In Cohort 2, a statistically significant and clinically meaningful improvement in OS was observed in patients with HRR-mutated mCRPC. At a median follow-up of 44.2 months, the median OS was 45.1 months with TALZENNA in combination with XTANDI, and 31.1 months with XTANDI and placebo (HR of 0.62; 95% CI, 0.48-0.81; p=0.0005), a 38% reduction in the risk of death. This result represents a 14-month gain in median OS versus standard of care XTANDI in a patient population with a historically poor prognosis. The OS improvement in the HRR-mutated population was observed in patients in both BRCA and non-BRCA gene alterations. Dr. Karim Fizazi, Institut Gustave Roussy, University of Paris-Saclay will share data from Cohort 2 at ASCO (Free ASCO Whitepaper) GU today (Abstract LBA141).
"Since its approval, TALZENNA in combination with XTANDI has redefined the standard of care for those living with homologous recombination repair gene-mutated mCRPC. These latest data from TALAPRO-2 are extremely compelling, demonstrating that the combination significantly extended overall survival, in patients selected and unselected for HRR gene alterations, potentially shifting the treatment paradigm for all men living with mCRPC," said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. "Although definitive conclusions cannot be drawn across studies, these results appear to represent the longest median overall survival reported in a randomized, controlled Phase 3 trial in mCRPC. We look forward to continuing to work with global authorities to potentially update the TALZENNA label with these results."
"TALAPRO-2 is the first study demonstrating a significant and clinically meaningful survival benefit using a combination of PARP and androgen receptor inhibitors in mCRPC," said Neeraj Agarwal, M.D., FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and global lead investigator for TALAPRO-2. "Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease. Today’s results demonstrate the potential for TALZENNA in combination with XTANDI to be a practice-changing treatment to help improve patient survival in mCRPC."
At the time of the final analysis, updated radiographic progression free survival (rPFS) and other secondary efficacy endpoints demonstrated maintained clinical benefit in both cohorts and were consistent with the primary analyses previously reported and published in The Lancet and Nature Medicine .
In addition to the FDA, these data have been shared with the European Medicines Agency (EMA) and other global health authorities to support potential updates of the approved labels for TALZENNA.
The safety profile of TALZENNA plus XTANDI was generally consistent with the known safety profile of each medicine. The most common all-cause adverse events in the TALZENNA group (≥30% of patients) were anemia, neutropenia, and fatigue, and the most common (≥10% of patients) grade 3–4 adverse events were anemia (49%) and neutropenia (19.3%). Adverse events were generally manageable with dose modification and supportive care.
About Metastatic Castration-Resistant Prostate Cancer
Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death among men worldwide, with an estimated 1.4 million new cases diagnosed in 2022.1 In the U.S., it is the most common cancer in men.2 mCRPC is a cancer that has spread beyond the prostate gland and has progressed despite medical or surgical treatment to lower testosterone. Approximately 10–20% of prostate cancer patients develop mCRPC within 5−7 years of diagnosis.3 Between 1.2–2.1% of all prostate cancer cases globally are mCRPC.4
About TALAPRO-2
The Phase 3 TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,035 unique patients with mCRPC who had not received new life-prolonging systemic treatments after documentation of mCRPC at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: unselected (n=805, of whom 169 had HRR mutations and 636 did not) and those with HRR gene mutations (n=399, including 169 patients from Cohort 1 and 230 subsequently enrolled to comprise Cohort 2). Patients with castrate testosterone levels were randomized to receive TALZENNA 0.5 mg/day plus XTANDI 160mg/day, or placebo plus XTANDI 160mg/day.
The primary endpoint of the trial was rPFS, defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent central review (BICR), or death, whichever occurred first, in both Cohort 1 (unselected) and Cohort 2 (those with HRRm). Secondary endpoints included OS, objective response rate (ORR), duration of response (DoR), prostate-specific antigen (PSA) response, time to cytotoxic chemotherapy and PFS2.
For more information on the TALAPRO-2 trial (NCT03395197), go to www.clinicaltrials.gov.
About TALZENNA (talazoparib)
TALZENNA is an oral inhibitor of poly ADP-ribose polymerase (PARP), which plays a role in DNA damage repair. Preclinical studies have demonstrated that TALZENNA blocks PARP enzyme activity and traps PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death.
TALZENNA was initially approved in the U.S., EU, and multiple other regions as a single agent for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer.
TALZENNA in combination with XTANDI was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with HRR gene-mutated mCRPC in June 2023. The combination was also approved by the European Commission in January 2024 for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated. TALZENNA is the first and only PARP inhibitor licensed in the European Union for use with XTANDI for patients with mCRPC, with or without gene mutations. TALZENNA in combination with XTANDI is now approved in more than 40 countries globally for patients with mCRPC, indications vary by country.
TALZENNA (talazoparib) Indication in the U.S.
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for:
HRR gene-mutated mCRPC:
In combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
Breast Cancer:
As a single agent, for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA.
TALZENNA (talazoparib) Important Safety Information
WARNINGS and PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with a fatal outcome, has been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as a single agent in clinical studies. In TALAPRO-2, MDS/AML occurred in 2 out of 511 (0.4%) patients treated with TALZENNA and enzalutamide and in 0 out of 517 (0%) patients treated with placebo and enzalutamide. The durations of TALZENNA treatment in these five patients prior to developing MDS/AML were 0.3, 1, 2, 3, and 5 years, respectively. Most of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.
Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor blood counts monthly during treatment with TALZENNA. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If counts do not recover within 4 weeks, refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.
Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. In TALAPRO-2, Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 45%, 18%, and 8% of patients receiving TALZENNA and enzalutamide. Overall, 39% of patients (199/511) required a red blood cell transfusion, including 22% (111/511) who required multiple transfusions. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 7%, 3%, and 0.4% of patients.
Withhold TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. Monitor blood counts monthly during treatment with TALZENNA. If hematological toxicities do not resolve within 28 days, discontinue TALZENNA and refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics.
Embryo-Fetal Toxicity TALZENNA can cause fetal harm when administered to pregnant women. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for 4 months after receiving the last dose.
ADVERSE REACTIONS
In TALAPRO-2, serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).
The most common adverse reactions (≥ 10%, all Grades), including laboratory abnormalities, for patients in the TALAPRO-2 study who received TALZENNA in combination with enzalutamide vs patients receiving placebo with enzalutamide were hemoglobin decreased (79% vs 34%), neutrophils decreased (60% vs 18%), lymphocytes decreased (58% vs 36%), fatigue (49% vs 40%), platelets decreased (45% vs 8%), calcium decreased (25% vs 11%), nausea (21% vs 17%), decreased appetite (20% vs 14%), sodium decreased (22% vs 20%), phosphate decreased (17% vs 13%), fractures (14% vs 10%), magnesium decreased (14% vs 12%), dizziness (13% vs 9%), bilirubin increased (11% vs 7%), potassium decreased (11% vs 7%), and dysgeusia (10% vs 4.5%).
Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).
Based on animal studies, TALZENNA may impair fertility in males of reproductive potential.
DRUG INTERACTIONS
Coadministration with P-gp inhibitors The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken in combination with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor.
Coadministration with BCRP inhibitors Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor. Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure, which may increase the risk of adverse reactions.
USE IN SPECIFIC POPULATIONS
Renal Impairment The recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 – 59 mL/min) is 0.35 mg taken orally once daily in combination with enzalutamide. The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 – 29 mL/min) is 0.25 mg taken orally once daily in combination with enzalutamide. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients requiring hemodialysis.
Please see full U.S. Prescribing Information and Patient Information for TALZENNA (talazoparib) at www.TALZENNA.com.
About XTANDI (enzalutamide) and Important Safety Information
XTANDI (enzalutamide) is an androgen receptor signaling inhibitor. XTANDI is a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic castration-sensitive prostate cancer (mCSPC; also known as metastatic hormone-sensitive prostate cancer or mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC) and nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). XTANDI is currently approved for one or more of these indications in more than 90 countries, including in the U.S., EU, and Japan. Over one million patients have been treated with XTANDI globally.6
What should I tell my doctor before taking XTANDI?
Tell your doctor about all your medical conditions, including if you:
Have a history of seizures, brain injury, stroke, or brain tumors.
Have a history of heart disease, have high blood pressure, or have abnormal amounts of fat or cholesterol in your blood (dyslipidemia).
Are pregnant or plan to become pregnant. XTANDI can cause harm to your unborn baby and loss of pregnancy (miscarriage).
Have a partner who is pregnant or may become pregnant.
Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with XTANDI and for 3 months after the last dose.
Males must use a condom during sex with a pregnant female.
Are breastfeeding or plan to breastfeed. It is not known if XTANDI passes into your breast milk.
Take other medicines.XTANDI may affect the way other medicines work, and other medicines may affect how XTANDI works. These include prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not start or stop any medicine without talking to your doctor.
How should I take XTANDI?
Take XTANDI exactly as your doctor tells you.Take your prescribed dose once a day, at the same time each day. XTANDI can be taken with or without food. Swallow XTANDI capsules or tablets whole with enough water to make sure that you can swallow all of the medicine successfully. Do not chew, dissolve, or open the capsules. Do not cut, crush or chew the tablets. Your doctor may change your dose if needed. Your doctor may also change your pill size or stop treatment if you have swallowing problems.
Do not change or stop taking your prescribed dose of XTANDI without talking with your doctor first.
If you are receiving gonadotropin-releasing hormone (GnRH) therapy, you should continue with this treatment while taking XTANDI unless you have had surgery to lower the amount of testosterone in your body (surgical castration).
If you miss a dose of XTANDI:Take your prescribed dose as soon as you remember that day. If you miss your daily dose, take your prescribed dose at your regular time the next day. Do not take more than your prescribed dose of XTANDI each day.
If you take too much XTANDI:Call your doctor or go to the nearest emergency room right away. You may have an increased risk of seizure if you take too much XTANDI.
What are the possible side effects of XTANDI?
XTANDI may cause serious side effects including:
Seizure.If you take XTANDI, you may be at risk of having a seizure. Avoid activities where a sudden loss of consciousness could seriously harm you or someone else. Tell your doctor right away if you lose consciousness or have a seizure.
Posterior Reversible Encephalopathy Syndrome (PRES).If you take XTANDI you may be at risk of developing a condition involving the brain called PRES. Tell your doctor right away if you have a seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision or other visual problems. Your doctor will do a test to check for PRES.
Allergic Reactions. Allergic reactions have happened in people who take XTANDI. Stop taking XTANDI and get medical help right away if you develop swelling of the face, tongue, lip or throat.
Heart Disease.Blockage of the arteries in the heart (ischemic heart disease) that can lead to death has happened in some people during treatment with XTANDI. Your doctor will monitor you for signs and symptoms of heart problems during your treatment. Call your doctor or go to the emergency room right away if you get chest pain or discomfort at rest or with activity or shortness of breath during your treatment with XTANDI.
Falls and Bone Fractures.XTANDI treatment may increase your risk for falls and bone fractures. Falls were not caused by loss of consciousness or seizures. Your doctor will monitor your risks for falls and bone fractures during treatment with XTANDI.
Swallowing problems or choking.Severe swallowing problems or choking, including life-threatening problems or death can happen in people during treatment with XTANDI, because of the size of the XTANDI capsules and tablets. Swallow each XTANDI capsule or tablet whole with enough water to make sure that you can swallow all of the medicine successfully.
Your doctor will stop treatment with XTANDI if you have serious side effects.
The most common side effects of XTANDI include:
Muscle and joint pain
Feeling more tired than usual
Hot flashes
Constipation
Decreased appetite
Diarrhea
High blood pressure
Bleeding problems
Falls
Bone fractures
Headache
XTANDI may cause fertility problems in males, which may affect the ability to father children. Talk to your doctor if you have concerns about fertility.
These are not all the possible side effects of XTANDI. For more information, talk to your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .