Back Back
PARPi for Prostate Cancer FAQ
PARP Inhibitors for Prostate Cancer: Expert Answers to Your Questions

Released: April 09, 2024

Expiration: April 08, 2025

Daniel P. Petrylak
Daniel P. Petrylak, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Sensitivity to PARP inhibition varies between HRR genes in metastatic CRPC, with mutations in BRCA1/2 being more sensitive, PALB2 partly sensitive, and ATM insensitive.
  • Patients may benefit from repeat somatic testing when disease switches from nonvisceral to visceral, which suggests a change in the somatic mutation profile.
  • When choosing between PARP inhibitor combination regimens, consider the patient’s mutation status and the safety profile of the ARPI in the regimen.

In this commentary, Daniel P. Petrylak, MD, answers questions posed by an audience of healthcare professionals during a webinar titled, “PARP Inhibition in Prostate Cancer: Optimizing Care for Veterans.” To date, the FDA has approved multiple PARP inhibitors for patients with metastatic castration-resistant prostate cancer (CRPC) harboring mutations in BRCA1/2. PARP inhibitors are approved as monotherapy (olaparib, rucaparib) or in combination with an androgen receptor pathway inhibitor (ARPI; niraparib plus abiraterone, olaparib plus abiraterone, and talazoparib plus enzalutamide). Olaparib monotherapy and talazoparib plus enzalutamide are also indicated for mutations affecting other genes in the homologous recombination repair (HRR) pathway.

Would you recommend a PARP inhibitor to patients with metastatic CRPC and an ATM or PALB2 mutation?
I would not recommend a PARP inhibitor for a patient with an ATM mutation. I would consider this drug class for one with a PALB2 mutation.

Both olaparib monotherapy and talazoparib plus enzalutamide are approved for patients with progressive metastatic CRPC harboring HRR gene mutations, including ATM and PALB2. However, gene subgroup analyses from clinical trials for multiple PARP inhibitors consistently show that ATM-mutated disease is not sensitive to PARP inhibition. For example, in the ATM-mutated subgroup on the phase III PROfound trial, the median radiologic progression-free survival was 5.36 months with olaparib vs 4.70 months when switching to a second ARPI. I would recommend that patients with ATM-mutated metastatic CRPC pursue a clinical trial.

PALB2 mutations are much rarer than ATM mutations, but clinical trial data indicate that PALB2 mutation imparts some sensitivity to PARP inhibition. In the PROfound trial, 1 of 3 patients with PALB2-mutated disease had a durable response to olaparib, with their radiologic progression-free survival lasting almost 10 months. In the phase II TRITON2 trial, all 4 patients with PALB2-mutated disease had a partial response to rucaparib. These data suggest that patients with PALB2-mutated metastatic CRPC may benefit from PARP inhibition, although their disease is not as sensitive as those with BRCA1/2 mutation.

Do you repeat testing for somatic BRCA1/2 mutations when a patient has disease progression?
I do try to repeat somatic testing when there is a clinical change, although it can be challenging to get repeated testing approved by insurance plans. For example, I try to repeat testing if the disease changes from nonvisceral to visceral, because that suggests there has been a change in the somatic mutation profile. I have seen somatic BRCA1/2 mutations develop in patients with disease progression.

It is worthwhile to consider repeat testing when a patient has very limited treatment options. Identifying a somatic HRR mutation may expand their options to include PARP inhibitor–based therapy.

How do you choose among approved PARP inhibitor combination regimens?
To date, there have been no head-to-head clinical trials comparing PARP inhibitor combinations. Without those comparative data, I look at the patient’s mutation status, as that determines their eligibility for the approved combinations. For example, a patient with metastatic CRPC and a BRCA1/2 mutation is eligible for all 3 approved combinations (niraparib plus abiraterone, olaparib plus abiraterone, and talazoparib plus enzalutamide), but a patient with an HRR mutation outside of BRCA1/2 may be eligible only for talazoparib plus enzalutamide.

The safety profile of the ARPI is another important deciding factor. Although clinical data do not indicate a difference in the safety profiles of various PARP inhibitors, there are important differences for abiraterone vs enzalutamide. Abiraterone must be given with prednisone, and together these increase the risk of high-grade hypertension. Enzalutamide also is associated with a small risk of hypertension, as well as headaches, dizziness, and falls.

I consider choosing between PARP inhibitor combination regimens to be similar to how we approach choosing a local therapy. The efficacy is likely to be similar between the options, and the decision rests largely on what adverse events and risks are tolerable to the patient.

Does gastrointestinal toxicity diminish after a few cycles of a PARP inhibitor?
Low-grade gastrointestinal toxicities are common with PARP inhibitors, with phase III trials of single-agent olaparib and rucaparib reporting nausea in 41% to 50%, diarrhea in 21% to 31%, and constipation in 18% to 27% of patients. Similar rates were reported in clinical trials of PARP inhibitor combination regimens.

I find that the duration of gastrointestinal toxicity varies between patients. Some do experience less over time, although many need supportive care and dose modifications. Typically, gastrointestinal toxicity diminishes when we provide antiemetics and dose reduce the PARP inhibitor, rather than waiting for the toxicity to go away on its own.

Your Thoughts?
In your current practice, what challenges do you face with incorporating PARP inhibitors into the care of patients with metastatic CRPC? Join the discussion by answering the polling question and posting a comment.

Continue

Poll

1.

Are you using PARP inhibitor plus ARPI combinations in your practice?

Submit