Study: Research on the PARP inhibitor talazoparib (Talzenna) for early-stage breast cancer is promising

IN-DEPTH REVIEW OF RESEARCH

Study background:

PARP inhibitors block the function of a DNA repair enzyme in cells. Tumor cells of people with inherited BRCA mutations or tumor cell that have acquired a BRCA mutation can be specifically targeted and destroyed by PARP inhibitors.

Two PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna) are approved for treatment of advanced or metastatic breast cancers for people with an inherited mutation in one of the BRCA genes. The OlympiAD trial of olaparib (Lynparza) and the EMBRACA trial of talazoparib (Talzenna) showed that treatment with these drugs lengthened the time until tumors grew and improved quality of life among metastatic breast cancer patients compared to patients treated with chemotherapy.

Since PARP inhibitors are useful for treating metastatic breast cancer patients, can they be used to treat earlier-stage breast cancer? Typically, patients with BRCA-positive, early-stage tumors have been treated with chemotherapy before or at the time of surgery, which improved outcomes, specifically by increasing the frequency of pathologically complete recovery (pCR) or the frequency of clinically undetectable cancer.

The I-SPY trial found improved outcomes when the PARP inhibitor velociparib was given with traditional chemotherapy (carboplatin plus paclitaxel) compared to another chemotherapy combination. Other combination trials with PARP inhibitors for early-stage breast cancer have not shown any improved outcomes; however, in these studies, most participants did not have BRCA mutations. If PARP inhibitors work predominantly in people with BRCA mutations this may have confused the results.

Could PARP inhibitors alone give a similar or better result than chemotherapy drugs for people with BRCA mutations?  Researchers at MD Anderson Cancer Center at the University of Texas tested whether tumors of patients with stage I to III breast cancer responded to the PARP inhibitor talazoparib (Talzenna) when it was given before other chemotherapy. Patients with BRCA mutations and stage I to III breast cancer who were treated with talazoparib for 2 months and then chemotherapy prior to surgery showed a decrease in tumor size.

This result led to this pilot study that looked at whether talazoparib by itself at the time of surgery improved patient outcomes with tolerable side effects.

Researchers of this study wanted to know:

whether patients with inherited BRCA mutations who were treated with talazoparib (Talzenna) alone for 6 months prior to surgery had undetectable tumors (a pathological complete response) and manageable side effects when compared to patients who were treated with other chemotherapy prior to surgery.

Populations looked at in this study:

Participants were 20 patients with a verified inherited BRCA1 or BRCA2 mutation, stage I to III breast cancer, and a primary tumor of 1 cm or larger that was imaged by mammogram and ultrasound. Participants were enrolled from August 2016 to September 2017, with a median age of 38 years (range: 23 to 58 years). Although both men and women were eligible, all 20 participants were women. Among the participants:

• 16 had a BRCA1 mutation
• 4 had a BRCA2 mutation
• 15 had triple-negative breast cancer
• 5 had hormone receptor-positive cancer
• 5 had stage I cancer
• 12 had stage II cancer,
• 3 had stage III cancer, including 1 patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma.

Patients with HER2+ tumors were excluded. Patients were also excluded if they had previous surgery, radiation, or systemic therapy for breast cancer. Patients with prior ductal carcinoma in situ or who had treatment for a previous non-breast cancer at least 5 years prior were still eligible.

Study design:

This pilot study of 20 patients intended to collect preliminary data to demonstrate the usefulness of a larger trial.

Twenty patients underwent a pretreatment biopsy, then took 1 mg of talazoparib once a day for 6 months, had surgery to remove their tumors and then had postsurgery treatment of their physician’s choice. The study measured residual cancer burden (RCB) or the amount of tumor that remains after treatment and tracked side effects among participants. Patients who had at least 4 months of talazoparib treatment and surgery within 6 weeks of their last dose were evaluated. One patient received 5 months of therapy, but had an enlarged lymph node and chose to have systemic chemotherapy before surgery. Her information was included for toxicity but not for the primary end point of pathologic response.

Study findings: 

The majority of patients treated with talazoparib (Talzenna) before surgery had a pathologic complete response [pCR]) or no invasive disease in breast and lymph at the time they were evaluated. The study measured residual cancer burden (RCB), the amount of tumor that remains after treatment. A RBC-0 is the same as pathologic complete response. Residual cancer burden of 1 (RCB-1) or more have increasing amounts of tumor remaining.

• 19 patients were evaluated for residual cancer burden
  • 10 of 19 (53%) had RCB-0 (pathologic complete response [pCR]) or no invasive disease in breast and lymph nodes)
  • 2 of 19 (10%) had RCB-I.
  • 5 of 19 (26%) had RCB-II.
  • 3 of 19 (16%) had RCB-III.
     
• 12 of 19 (63%) of participants had a low amount or no residual tumor (RCB-0/I).
   
• The majority of participants with either triple negative or HR-positive breast cancer had low or no residual tumor (RCB-0/I).
  • Among participants with triple-negative breast cancer, 57% had low or no residual tumor (RCB-0/I).
  • Among participants with HR-positive breast cancer, 80% had low or no residual tumor (RCB-0/I).
     
• Among participants with T1 tumors, 83% had low or no residual tumor (RCB-0/I).
• Among participants with T2 or greater tumors, 54% had low or no residual tumor (RCB-0/I).
   
• Among participants with BRCA1 mutations, 53% had low or no residual tumor (RCB-0/I).
• Among participants with BRCA2 mutations, 100% had low or no residual tumor (RCB-0/I).
   
• The single patients with metaplastic chondrosarcomatous carcinoma, invasive lobular carcinoma, or inflammatory breast cancer all had had no detectable tumor remaining (pCR/RCB-0).

The toxic side effect observed were tolerable tor most patients.
 

• 11 of 20 (55%) patients completed the trial on the full dose of talazoparib.
• 9 of 20 (45%) patients had their doses reduced due to treatment-related anemia.
   
• Patients with severe toxic side effects (grade 3 or 4) either had doses of talazoparib reduced by 0.25 mg increments until their side effects were manageable or had a blood transfusion.
  • 2 patients had their dose reduced to 0.75 mg per day
  • 6 patients had their dose reduced to 0.5 mg per day
  • 1 patient had their dose reduced to 0.25 mg per day

The most common less severe side effects were nausea, fatigue, anemia (low red blood cell count), hair loss, dizziness and breathing difficulties.
 

The most common severe side effects were anemia and nausea:

• 12 of 20 (40%) participants had severe (grade 3 or 4) toxicities
  • 8 patients had severely low red blood cell numbers (grade 3) and required a transfusion.
  • 3 patients had severely low white blood cell numbers (grade 3).
  • 1 patient had very severely low platelet numbers (grade 4).

Limitations:

This trial had many limitations:

• This was a preliminary study with only 20 participants, intended as a pilot test to determine whether a larger trial was justified. The results are promising, but the numbers are too small to be certain how much is a fluke. A larger study is needed to validate these results.
   
•  Only a single institution was involved in this study. It is possible that there are additional confounding factors about treatment at this institution that may account for the results. A larger study would ideally be run at multiple institutions to reduce this possibility.
   
• This trial had no comparison intervention. The number of participants who had  complete reduction of tumor burden (RCB-0) or low residual tumor burden (RCB-1) are promising but can only be compared to data in trials run in other places and under other circumstances. A direct comparison of this treatment regimen versus a current standard treatment is needed to know if this treatment protocol is comparable, better, or worse than chemotherapy for early-stage cancer treatment.
   
• No patient-reported outcome tests were done. Researchers did ask about changes in menstrual cycles, but did not measure the state of participants’ fertility. The researchers point out that many BRCA mutation carriers are young and still in the process of family planning. This type of information would be an important addition to future studies.
   
• Postsurgical treatment in this trial was left up to the surgeon/oncologist's choice. Having a more controlled trial that evaluated specific postsurgical treatments in comparison to PARP inhibitor treatment would be clarifying.

Conclusions:

In this pilot study, Talzenna (talazoparib) alone appears to be a promising treatment for patients with BRCA mutations who develop early-stage breast cancer. An expanded clinical trial with a larger number of participants is needed to determine if this treatment approach is viable.

Share your thoughts on this XRAYS article by taking our brief survey.

Posted 10/4/19