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Experts Answer Your Pressing Questions on PARP Inhibitors in Metastatic Prostate Cancer

Released: April 15, 2026

Wassim Abida
Wassim Abida, MD, PhD
Nabil Adra
Nabil Adra, MD, MS
Neeraj Agarwal
Neeraj Agarwal, MD, FASCO
Kristine Peregrino Lacuna
Kristine Peregrino Lacuna, MD
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Key Takeaways
  • Biomarker testing is important for identifying patients with metastatic prostate cancer who may benefit from the use of targeted agents like PARP inhibitors.
  • PARP inhibitors (olaparib, niraparib, talazoparib, rucaparib) are approved alone or in combination with androgen receptor pathway inhibitors for metastatic prostate cancer.
  • Anemia is common with PARP inhibitors but manageable with dose adjustments.

In this commentary, Wassim Abida, MD, PhD, Nabil Adra, MD, MS, Neeraj Agarwal, MD, FASCO, and Kristine Peregrino Lacuna, MD, address key questions posed by the audience during a recent satellite symposium titled, “Precision in Practice: A Master Class on PARPi Combinations, Testing Strategies, and Toxicity Management in Metastatic Prostate Cancer.” During this symposium, expert faculty reviewed best practices for biomarker testing in patients with metastatic prostate cancer and the latest safety and efficacy data on PARP inhibitor use.

What approach do you take when next-generation sequencing from bone biopsies fails?
Wassim Abida, MD, PhD: Bone biopsies can be challenging for molecular testing. Tumor content is variable, and bone samples are often decalcified, which results in degradation of DNA. Next-generation sequencing on bone biopsy samples fails about half of the time, including at expert centers that use PET for target localization.

In case of failure, the options for somatic testing are to rebiopsy the patient or use cell-free DNA, which is easiest. For a patient with aggressive disease, there is typically a high amount of circulating tumor DNA content in their cell-free DNA. This is ideal because with liquid biopsy, the results are highly dependent on tumor burden.

How do you address concerns for clonal hematopoiesis of indeterminate potential (CHIP) interference with liquid biopsy?
Neeraj Agarwal, MD, FASCO: Liquid biopsies are convenient because they only require a blood sample, but they also have some challenges. CHIP interference can happen in approximately 10% of cases when circulating tumor DNA is used for biomarker testing. CHIP can cause false positivity for ATM mutations and some CHEK2 mutations.

Wassim Abida, MD, PhD: Different laboratories use different thresholds for classifying clonal hematopoiesis as mutations. Results will depend on whether the assay sequences the white blood cells (buffy coat) because that is where you can more reliably identify CHIP. If buffy coat is used, CHIP interference can be filtered out, but many commercial assays do not include this step. They may be calling alterations at very low allele frequency actionable mutations.

If I see ATM and CHEK2 at very low allele frequency, I suspect clonal hematopoiesis. Also, mutations that are commonly detected but present at very low levels may not be clinically meaningful. When in doubt, I think if it looks like an actionable mutation, I will want to take the option to treat with a targeting therapy.

How can we address the high treatment attrition rate in metastatic castration-resistant prostate cancer (mCRPC)?
Neeraj Agarwal, MD, FASCO: In the real-world setting, approximately 50% of patients with mCRPC will not be able to receive subsequent lines of therapy. One way to address this is to ensure that we have biomarker testing done in the metastatic hormone-sensitive setting or whenever we first see a patient. It can take weeks for a patient to get a biopsy and several more weeks for us to receive the results. If the results are negative or there is insufficient testing, we then lose time doing another biopsy and additional biomarker testing. If we do biomarker testing for all patients upfront, we avoid having to test for actionable targets when their disease is progressing rapidly in the mCRPC setting.

How would you treat a patient who was diagnosed with de novo metastatic hormone-sensitive prostate cancer (mHSPC) with a BRCA2 mutation who was treated with ADT plus abiraterone and now has progressive disease?
Kristine Peregrino Lacuna, MD: There may not be 1 right or wrong answer here. For single-agent PARP inhibitors, rucaparib was approved in the post–androgen receptor pathway inhibitors (ARPI) setting based on results from phase II TRITON2 and phase III TRITON3. In these trials, rucaparib monotherapy showed superior median progression-free survival (PFS) results when compared with physician’s choice in a population of patients with progressive disease on an ARPI. In the phase III PROfound trial, the efficacy of olaparib was investigated in 2 cohorts of patients with mCRPC, one including patients with BRCA1/2 or ATM alterations and another with other homologous recombination repair (HRR) mutations. Olaparib monotherapy resulted in superior median PFS and median overall survival (OS) when compared with physician’s choice in those with BRCA1/2 or ATM alterations. The phase III MAGNITUDE trial also supports the use of niraparib plus AAP (abiraterone acetate plus prednisone) for this patient. In this trial, niraparib plus AAP improved median PFS in the BRCA-positive subgroup over AAP alone. Enrolled patients were allowed to receive prior abiraterone treatment, although the population was small, at approximately less than 4%. Finally, talazoparib plus enzalutamide is an option for this patient based on the results of the phase III TALAPRO-2 trial, where 6.5% of patients received prior ARPI treatment. Talazoparib plus enzalutamide resulted in improved PFS and OS when compared with placebo plus enzalutamide. These are all available and reasonable options for this patient. We would need to further consider a single agent vs a combination-based regimen based on the individual patient, the patient’s disease, comorbidities, and survival benefit.

Nabil Adra, MD, MS: I agree with Dr Lacuna. The priority is that this patient receives a PARP inhibitor as their next line of therapy, either as a single agent or in combination with an ARPI.

Wassim Abida, MD, PhD: I would not continue a regimen that includes abiraterone. I would go with a category 1 recommendation from the NCCN guidelines, which is either rucaparib or olaparib. I also think talazoparib plus enzalutamide is a reasonable choice here, although there is an unanswered question of the benefit of enzalutamide being added to a PARP inhibitor in this setting (following progression on a prior ARPI). Hopefully, this can be teased out in the phase II TALENT trial (NCT06844383), which is evaluating talazoparib with or without enzalutamide in patients with mCRPC who have HRR mutations who received abiraterone for mHSPC or locally advanced disease.

How do you manage anemia in patients with mCRPC receiving talazoparib plus enzalutamide?
Neeraj Agarwal, MD, FASCO: My hypothesis, based on the earlier PK/PD studies with talazoparib and enzalutamide, is that in some patients, talazoparib concentration rises in the presence of enzalutamide, and these are the patients who develop grade 3 anemia. Grade 3 anemia happens early during the course of treatment and occurs in approximately 50% of patients. The recommended approach is to hold the drug, manage symptoms via blood transfusion, and then reduce the dose. I also check blood counts monthly and check vitamin B12, folate, and iron levels for patients starting these therapies.

Nabil Adra, MD, MS: I take a similar approach where we check CBCs monthly. I also set expectations with the patient. I let them know that there is a 50% chance they will develop severe anemia, and if that happens, we will hold the drug, transfuse, and dose reduce. The patients who have a dose reduction do very well. I have never had a patient discontinue talazoparib due to anemia.

Wassim Abida, MD, PhD: There does seem to be a higher toxicity rate with the combination of talazoparib and enzalutamide, and I also think it could be because of the drug interaction. When used with enzalutamide, talazoparib is dosed at 0.5 mg, which is half the monotherapy dose. But the rate of grade 3 anemia with the combination is almost double what we would expect with monotherapy. We have to be vigilant about managing anemia. Another thing to note is that with combination regimens, we have to tease out the toxicities. In some cases, we may need to dose reduce each drug independently. If I see a patient with grade 2 anemia that is trending down, I would consider a dose reduction of talazoparib. But, if fatigue seems out of proportion for the grade of anemia, I would consider reducing the enzalutamide dose. As we know, enzalutamide causes fatigue and cognitive toxicity.

Your Thoughts
What other questions do you have about biomarker testing or the use of PARP inhibitors in the management of your patients with metastatic prostate cancer with HRR alterations?

For an opportunity to get your questions on PARP inhibitors answered by expert faculty, join us for an encore webinar of this satellite symposium on Thursday, April 23, by registering here.

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