Study: PARP inhibitor treatment for metastatic prostate cancer shows most benefit in men with inherited BRCA mutations

IN-DEPTH REVIEW OF RESEARCH

Study background

Researchers conducting the GALAHAD study wanted to know if the PARP inhibitor niraparib is an effective and safe treatment for people with metastatic castration-resistant prostate cancer (mCRPC) and homologous DNA repair deficiency. 

Populations looked at in this study

The GALAHAD study took place in 115 hospitals in 15 countries. The study began with 2,898 participants aged 64 to 74 years with metastatic castration-resistant (treatments that lower testosterone levels are no longer sufficient for disease control) prostate cancer (mCRPC). Most participants (71%) were white.

All participants had prior prostate cancer treatment, and their cancer continued to grow despitetreatment. Participants were excluded if they had previously been treated with a PARP inhibitor or platinum-based chemotherapy.

The participants were divided into two groups:

• The BRCA cohort had germline or acquired mutations in BRCA1 or BRCA2 (most had a BRCA2 mutation).
• The non-BRCA cohort had germline or acquired mutations in ATM, BRIP1, CHEK2, FANCA, HDAC2 or PALB2. Within the two cohorts, participants were further divided as having measurable disease or non-measurable disease.

Most participants were white but a significant proportion (17%) were of unknown or unreported ethnicity.

Study design

GALAHAD was a phase 2 study exploring the potential effectiveness and safety of niraparib. The study had a single arm: All participants were prescribed niraparib 300 mg per day, which was given as oral capsules. In order to assess the effectiveness of niraparib, the response rate for measurable disease was assessed using CT scans to measure tumors at sites of metastatic disease. Safety was assessed by reporting adverse events that occurred between the date of the first dose of treatment and 30 days after the last dose of niraparib.

Study findings

Effectiveness of niraparib:

• During treatment with niraparib, study visits occurred weekly for the first month, biweekly for the second month and monthly thereafter.
  • CT or MRI and technetium bone scans were performed during visits every 8 weeks for 24 weeks and then every 12 weeks thereafter.
  • Circulating tumor cells were assessed every treatment cycle until cycle 7 and then at the end of treatment.
  • PSA tests were done every 4 weeks until cycle 7 and then every three weeks after that.
• In a subset of 76 men with BRCA1 or BRCA2 mutations and measurable disease, 26 (34.2%) had tumors that demonstrated response on CT scans to niraparib therapy. Of the 26 men whose tumors showed response to niraparib, 8 experienced tumor responses that were ongoing as of the most recent data collection.
• Men in the BRCA cohort with non-measurable disease (as defined by the study protocol) responded to niraparib, based on blood tests and bone scan findings. 
• Only 10.6% (5/47) of the non-BRCA cohort with measurable disease responded to niraparib.
• Overall survival was longest for participants in the BRCA cohort with measurable disease.
• Two patients in the measurable BRCA cohort achieved a complete response, compared to no patients achieving complete response in the non-BRCA cohort.

Safety of niraparib:

• Adverse events were similar to those seen in patients who are treated with niraparib for other cancers.  
• Nausea and anemia were the most common adverse events overall and were experienced by most participants (58% and 54%, respectively).
• Other common adverse events included fatigue, vomiting, thrombocytopenia, constipation, decreased appetite, neutropenia and back pain.
• Serious adverse events (grade 3 or higher) were experienced by two-thirds of patients. Most serious adverse events were hematologic: anemia, thrombocytopenia and neutropenia.
• Two fatal adverse events may have been related to niraparib: urosepsis in the BRCA cohort and sepsis in the non-BRCA cohort.

Strengths and limitations

Strengths:

• The GALAHAD study is a multi-center, multi-country study. 
• All patients received the same treatment. All participants had been treated similarly prior to the beginning of this study.

Limitations:

• 9% (7 of 76) of patients experienced disease progression before their first study evaluation and discontinued treatment.
• About a quarter of participants had tumor mutations in TP53, which are associated with an overall poor prognosis.

• 89% of the participants in the BRCA group had a BRCA2 mutation, so it is unclear whether those with BRCA1 mutations would respond similarly or not.

Context

PARP inhibitor therapy with olaparib and rucaparib has been FDA-approved for mCRPC in people with inherited BRCA1 and BRCA2 mutations. Niraparib is a PARP inhibitor currently approved for ovarian cancer treatment. In the ovarian cancer setting, it is used to treat ovarian tumors with and without BRCA gene defects. Researching whether niraparib is potentially effective and safe for people with mCRPC who have inherited BRCA mutations or inherited or acquired mutations in other genes is consistent with the current knowledge about potential anti-tumor activity by PARP inhibitors.     

Conclusions

Niraparib shows promise as a potential treatment for mCRPC, especially for people with inherited or acquired BRCA1 or BRCA2 mutations. Further study is needed to more fully determine the effectiveness of niraparib in the treatment of mCRPC tumors.

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posted 9/6/2022