Talazoparib for prostate cancer and breast cancer

Background:
The body has several mechanisms for repairing breaks in strands of DNA. One mechanism is homologous recombination repair (HRR). Mutation of genes involved in HRR, such as BRCA1 and BRCA2 (BReast CAncer genes 1 and 2), are associated with increased risk of a range of cancers, including breast, ovarian, pancreatic and prostate cancer.

Another DNA repair mechanism involves the poly (ADP-ribose) polymerase (PARP) enzymes. In people with susceptible cancers, especially with HRR gene defects, inhibition of PARP increases DNA damage in the cancer cells and results in cell death. Olaparib and niraparib are PARP inhibitors that were approved in 2016 and 2021, respectively.

Talazoparib is a PARP inhibitor that was approved in 2019 (but not immediately brought to market) for the treatment of advanced or metastatic breast cancer with BRCA gene mutations. In 2024 it was approved for the treatment of patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC), in combination with enzalutamide, and has now been brought to market in Australia.

Mechanism of action:
In addition to inhibiting PARP as described above, talazoparib traps PARP enzymes on the damaged DNA, further impeding DNA repair in cancer cells.

There is potential for synergy between PARP inhibitors and androgen receptor pathway inhibitors, such as enzalutamide, in the treatment of prostate cancer.¹

Clinical trials:
The phase 3 trial of talazoparib in prostate cancer (TALAPRO-2) was a double-blind study of 1035 men with mCRPC.¹ Patients were randomised to receive once-daily treatment with talazoparib 0.5 mg and enzalutamide 160 mg or placebo and enzalutamide 160 mg. Treatment continued usually until either disease progression or adverse event leading to discontinuation. Among the participants were 399 men with alterations in HRR genes (most commonly BRCA1, BRCA2, ATM or CDK12*). After a median follow-up of approximately 17 months, the objective (radiological) response rate was 67% with the combination of talazoparib and enzalutamide versus 40% with placebo and enzalutamide.¹ Although complete results were not available at the time of writing, at median 44 months follow-up the TALAPRO-2 trial showed an overall survival advantage with the combination of talazoparib and enzalutamide (45.1 months) compared with placebo and enzalutamide (31.1 months).²

The main study of talazoparib in breast cancer was the open-label, randomised phase 3 EMBRACA trial.³ This trial compared talazoparib with a standard protocol-driven single-drug chemotherapy regimen chosen by the treating physician in 431 patients (98% female) with the BRCA 1 or 2 mutation and either locally advanced breast cancer that was not amenable to curative therapy or metastatic breast cancer; 44% had triple-negative cancer.† They had already been treated with up to 3 cytotoxic regimens. Treatment usually continued until toxicity became unacceptable or imaging showed cancer progression. The median treatment duration was 6.9 months with talazoparib and 3.9 months with standard therapy. A response to treatment occurred in 62.6% of patients in the talazoparib group and 27.2% in the standard therapy group. After a median follow-up of 11.2 months, radiological progression-free survival was 8.6 months and 5.6 months, respectively.³ There was no significant difference in overall survival, even after adjusting for subsequent therapy received (hazard ratio 0.76, 95% confidence interval 0.50 to 1.03), but there was improvement in patient-reported outcomes.⁴

Adverse effects:
The actions of talazoparib are not limited to cancer cells and myelosuppression is very common. In the TALAPRO-2 trial, 65% of the patients taking talazoparib developed anaemia (with 36% requiring blood transfusions) compared with 16% of those taking the placebo and enzalutamide combination.^1,5 The pattern of myelosuppression was similar in the EMBRACA trial.^3,4 Other very common adverse effects include fatigue and nausea. Adverse effects in talazoparib-treated patients in the TALAPRO-2 trial led to dose reduction (52%) or permanent discontinuation of therapy (10.1%), most commonly due to anaemia.

Dosage and administration:
The recommended talazoparib dose in prostate cancer is 0.5 mg orally once daily (in combination with enzalutamide 160 mg orally once daily). This is lower than the 1.0 mg recommended dose in breast cancer, because talazoparib concentrations are increased by an interaction with enzalutamide. Treatment (if tolerated) is usually continued until disease progression occurs.

Dose reduction is recommended for patients with moderate or severe renal impairment and to manage adverse effects. Low concentrations of haemoglobin, neutrophils or platelets require treatment to be withheld until concentrations recover. Talazoparib should be discontinued if more than 3 dose reductions are required.

Precautions:
Full blood counts should be taken before starting talazoparib and then at least monthly. Although talazoparib is mainly excreted unchanged in the urine, it is a substrate of the P-glycoprotein drug transporter. Drugs that inhibit P-glycoprotein (e.g. erythromycin, ketoconazole, verapamil) will therefore increase talazoparib concentrations. If co-administration cannot be avoided, the dose of talazoparib should be reduced.

Use in pregnancy and breastfeeding:
Talazoparib has cytotoxic effects, so it is unsuitable for use in pregnancy and lactation. Fertility could also be affected. Effective contraception is required during treatment of men and women and should continue for several months post-treatment.

Place in therapy:
The precise role of talazoparib in prostate cancer requires further elucidation. In TALAPRO-2 the combination of talazoparib and enzalutamide was used as first-line therapy for mCRPC.⁶ The benefit of using talazoparib in patients who have already received enzalutamide, or a similar drug, is unclear. There are currently no head-to-head trials comparing talazoparib plus enzalutamide to other treatment options; however, a network meta-analysis suggested the combination may have greater efficacy than some other treatments for outcomes such as response rate and radiological progression-free survival, although any comparative advantage in overall survival remains uncertain.⁷

In the TALAPRO-2 trial, talazoparib also had a positive effect in men with prostate cancer without HRR abnormalities;⁶ however, in Australia, it is only approved for men with HRR mutations. The role of talazoparib in men with metastatic castration-sensitive prostate cancer is being investigated in the phase 3 TALAPRO-3 trial.

In breast cancer, talazoparib is not a first-line treatment. Although the EMBRACA trial showed that radiological progression-free survival was increased, there was no improvement in overall survival.⁴ Patients in the trial had to have been previously treated with a taxane, an anthracycline, or both. This requirement is not included in the Australian approved indication for talazoparib in breast cancer. The EMBRACA trial did not compare talazoparib with platinum-based chemotherapy, which can be an option in advanced breast cancer. Further studies are needed to establish the optimum sequence for using PARP inhibitors and whether combining them with other drugs will improve outcomes.

* ATM = ataxia-telangiectasia mutated; CDK12 = cyclin-dependent kinase 12

† Triple-negative breast cancer is a type of breast cancer that does not express estrogen, progesterone, or human epidermal growth factor receptor 2 (HER2) receptors.

This new drug comment was finalised on 19 May 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration (published 2019, breast cancer indication only). The sponsor did not provide the Clinical Evaluation Report.

 

References

1. Fizazi K, Azad AA, Matsubara N, Carles J, Fay AP, De Giorgi U, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med 2024;30:257-64.
2. Agarwal N, Azad A, Carles J, Fay AP, Matsubara N, Szczylik C, et al. Final overall survival (OS) with talazoparib (TALA) enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Journal of Clinical Oncology 2025;43. .
3. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018;379:753-63.
4. Litton JK, Hurvitz SA, Mina LA, Rugo HS, Lee KH, Goncalves A, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol 2020;31:1526-35.
5. Azad AA, Fizazi K, Matsubara N, Saad F, De Giorgi U, Joung JY, et al. Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: Safety analyses from the randomized, placebo-controlled, phase III TALAPRO-2 study. Eur J Cancer 2024;213:115078.
6. Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet 2023;402:291-303.
7. Castro E, Ellis J, Craigie S, Haltner A, Nazari J, Niyazov A, et al. Comparative efficacy and safety of talazoparib plus enzalutamide and other first-line treatments for metastatic castration-resistant prostate cancer. Oncologist 2025;30.

 

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