Study: Promising early results for treating metastatic prostate cancer

Contents

STUDY AT A GLANCE

What is this study about?

The TALAPRO-1 study showed that talazoparib is a safe and effective treatment for metastatic castration-resistant prostate cancer (mCRPC) in people with mutations in DNA repair genes. The ongoing TALAPRO-2 study is looking at how well talazoparib together with the androgen receptor inhibitor enzalutamide worked to treat mCRPC in people with or without mutations in DNA repair genes.

Why is this study important?

Metastatic castration-resistant prostate cancer (mCRPC) no longer responds to standard treatments that block testosterone. People with mCRPC that continues to grow despite treatment have limited treatment options. More effective treatments are needed.

Talazoparib (Talzenna) is in a class of drugs called PARP inhibitors. PARP inhibitors have been useful in the treatment of several breast, ovarian, pancreatic and prostate cancers associated with inherited mutations or tumor mutations in DNA repair genes. Talazoparib is FDA-approved to treat breast cancer, but it is not yet received approval for prostate cancer treatment.

TALAPRO-2 is an ongoing study looking at how well talazoparib combined with the androgen receptor inhibitor enzalutamide (Xtandi) works to treat mCRPC in people with or without inherited or tumor mutations in DNA repair genes.

Study findings

This review covers results from the TALAPRO-1 study and the early results from the TALAPRO-2 study.

TALAPRO-1 

TALAPRO-1 showed that talazoparib has acceptable safety and is effective for treating people who have mCRPC with inherited mutations or tumor mutations in DNA repair genes.

Results of TALAPRO-1

• 31 of 104 (30%) participants’ cancers decreased in size.
• Cancers decreased in size only in participants with BRCA1, BRCA2, PALB2 or ATM mutations.
  • Cancer response rates were best among participants with BRCA1 or BRCA2 mutations—almost half of these participants' tumors responded to talazoparib.
• None of the 22 participants with mutations in ATR, CHEK2, FANCA, MLH1, MRE11A, NBN or RAD51C had decreased cancer size.  
• No significant safety issues occurred when participants took talazoparib.
• Side effects were common but similar to earlier studies of PARP inhibitors.
  • Nearly half of the participants had low red blood cell counts, which was the most common side effect.
  • Other common side effects of talazoparib were:
• nausea
• decreased appetite
• weakness
• low platelet counts
• low white blood cell counts
• No treatment-related deaths occurred.

TALAPRO-2

The TALAPRO-2 study is comparing treatment with talazoparib together with enzalutamide to treatment with enzalutamide alone in people with or without mutations in DNA repair genes. Early TALAPRO-2 results were reported at the American Society of Clinical Oncology Genitourinary Cancers Symposium in February of 2023. 

Early results of TALAPRO-2

Talazoparib plus enzalutamide significantly improved progression-free survival, regardless of mutation status when this combination was used as a first-line treatment for mCRPC. 

Among participants who received talazoparib plus enzalutamide (402), progression-free survival was 37 percent better compared to participants (403) who received enzalutamide alone. However, participants with a mutation in a DNA repair gene benefited more than those without a mutation.

• Preliminary progression-free survival was significantly improved for the talazoparib group compared to 22 months for participants who received enzalutamide alone (however data is not complete for the talazoparib plus enzalutamide group)
• Progression-free survival was improved among participants who received talazoparib plus enzalutamide compared to those who received enzalutamide alone, regardless of their mutation status.         
  • Among participants with inherited or tumor mutations in a DNA repair gene, progression-free survival was 28 months for those who received talazoparib plus enzalutamide compared to 16 months for those who received enzalutamide alone. 
  • Among participants with no known inherited or tumor mutation in a DNA repair gene, progression-free survival has not been achieved among those who received talazoparib plus enzalutamide compared to almost 23 months for those who received enzalutamide alone.
• Although the overall survival data is not complete, it is so far favoring those who received talazoparib plus enzalutamide compared to those who received enzalutamide alone.
• The time to reduced quality of life was significantly longer in the talazoparib plus enzalutamide group (31 months) compared to the enzalutamide alone group (25 months).
• Side effects were seen in 80% of patients taking talazoparib plus enzalutamide and in 41% of patients taking enzalutamide alone.
  • The most common side effects were anemia and certain low blood cell counts in the talazoparib plus enzalutamide arm. Hypertension, anemia and fatigue were the most common side effects in the placebo arm.

Conclusions

Two PARP inhibitors have been approved by the FDA for treating mCRPC. The PARP inhibitor olaparib (Lynparza) is approved to treat mCRPC that has progressed on the drugs enzalutamide or abiraterone (Zytiga) in people with a mutation in BRCA1, BRCA2, ATM or another gene linked to a certain type of DNA damage repair. The PARP inhibitor rucaparib (Rubraca) is approved to treat mCRPC in people who have an inherited mutation in BRCA1 or BRCA2 (found through genetic testing) or a tumor mutation in BRCA1 or BRCA2 (found through tumor testing or liquid biopsy).

While talazoparib does not have FDA approval to treat prostate cancer, the FDA has granted Priority Review for talazoparib plus enzalutamide for the treatment of mCRPC.

Strengths and limitations

Strengths

• TALAPRO-2 is a large multi-site study being conducted in 26 countries and 32 states in the U.S. that includes people from diverse backgrounds. It is double-blinded to participants and their providers.
• The results of TALAPRO-2 will address the limitations of TALAPRO-1.

Limitations

• TALAPRO-1 was a small early-phase study where all participants received the same treatment. It was not designed to determine whether talazoparib works better than other treatments. Participants could have mutations in one of 11 genes. The number of participants was too small to identify differences between responses in people with different mutations.
• The majority (87%) of TALAPRO-1 participants were white; given the small study size, this limits the ability to conclude whether talazoparib works similarly in people of all racial and ethnic backgrounds.

What does this mean for me?

While TALAPRO-2 is ongoing, these early results show significantly improved progression-free survival among participants who received talazoparib plus enzalutamide compared to participants who received enzalutamide alone. While this was true regardless of whether a participant had an inherited or tumor mutation in genes involved in DNA repair, the benefit is more apparent in patients who did have inherited or tumor mutations in DNA repair genes. Side effects do occur and drug cost should be considered.  Final overall survival information that is underway will be important to evaluate to determine when the combination may be most appropriate. While not yet FDA-approved, this combination may become a new standard of care option for people with mCRPC.

If you have been diagnosed with mCRPC and your cancer has progressed on standard care, genetic testing and tumor testing may help you learn if you would benefit from treatment with either rucaparib or olaparib; both are approved PARP inhibitors. You may also qualify for a research study looking at PARP inhibitors or other treatments for mCRPC.

Reference

de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264.

Agarwal N, Azad A, Shore ND, et al. Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design. Future Oncol. 2022;18(4):425-436.

Agarwal N, Azad A, Carles J et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 41, 2023 (suppl 6; abstr LBA17).

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 3/1/23