Mutation Status Drives PARP Inhibitor Investigation and Treatment in mCRPC

Atish D. Choudhury, MD, PhD

PARP inhibitors, such as olaparib (Lynparza) and talazoparib (Talzenna), as monotherapies or in combination with androgen receptor (AR) pathway inhibitors may broaden treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) with gene alterations within the homologous recombination–deficient pathway, according to Atish D. Choudhury, MD, PhD.

“There are controversies around the use of PARP inhibitors in mCRPC,” Choudhury said in an interview with OncLive®. “This class of agents is approved for the treatment of patients with metastatic prostate cancer with homologous recombination repair [HRR] defects [and can be used] as monotherapies in these patient populations.”

PARP inhibitors have produced favorable outcomes compared with hormone therapies in trials such as the phase 3 PROfound study (NCT02987543), in which patients with mCRPC with alterations in BRCA1, BRCA2, or ATM who received olaparib exhibited a median imaging-based progression-free survival of 7.4 months vs 3.6 months in those who received physician’s choice of enzalutamide (Xtandi) or abiraterone acetate (Zytiga).1Additionally, preliminary results from the phase 3 MAGNITUDE trial (NCT03748641), which investigated niraparib (Zejula) plus abiraterone acetate and prednisone in patients with mCRPC, showed that the combination reduced the risk of progression or death by 47% in patients with BRCA1 or BRCA2 mutations and 27% in those with all other HRR gene alterations.²

In the interview, Choudhury discussed the significance of these trials within the mCRPC treatment landscape, highlighted investigative PARP inhibitor combinations, and emphasized the need for further research in this area to determine which patients are most likely to benefit from certain therapies based on their molecular profiles.

Choudhury is the chair of the Gelb Center for Translational Research and a senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive^®: What are the current aims of research with PARP inhibitors in mCRPC?

Choudhury: [One common question is]: Who are the patients who are most likely to benefit [from these therapies]? Recent evidence [has also emerged regarding] the use of these agents in combination with potent AR pathway inhibitors. [We are also asking]: Who are the patient populations [most likely] to benefit from those combinations?

What clinical trials support the use of these agents in mCRPC? 

In the PROfound trial, patients with mCRPC with DNA damage repair defects were randomized to receive olaparib monotherapy vs physician’s choice of another hormonal drug. The [phase 2] TRITON2 trial [(NCT02952534) investigated] rucaparib [Rubraca] in mCRPC.

More recently, data have been presented with these PARP inhibitors in combination with AR pathway inhibitors. The [phase 3] PROpel study [(NCT03732820) combined] olaparib with abiraterone acetate, and the MAGNITUDE trial [investigated] niraparib plus abiraterone acetate. Additionally, a press release [was published in October 2022 with topline results from the phase 3] TALAPRO-2 study [NCT03395197] with talazoparib plus enzalutamide.

There’s much controversy regarding how we should treat these patients, but [the data from these trials can help us] draw conclusions about who is likely to benefit [from which therapies].

What toxicities and quality of life complications should clinicians be aware of when considering PARP inhibitor combinations in their patients?

The key question is: Which patient populations will benefit [from which therapies]? [Can genomic profiling detect] biomarkers other than the basic HRR deficiency defects that would predict the likelihood of benefit?

Additionally, who are the patients in whom [PARP inhibitors] might cause harm? The combination of PARP inhibitors and AR pathway inhibitors incurs a huge pill burden. It’s often 4 pills a day of each class of drug. There are additional toxicities when you use these in combination, and there are additional costs as well.

We don’t want to subject patients to a therapeutic strategy that they’re unlikely to benefit from. We also need to think about their overall disease status, disease burden, and comorbidities. Cost is also a definite consideration here. When we make recommendations for individual patients, we need to keep all this in mind.

What novel PARP inhibitor strategies are under investigation in mCRPC?

The major advances in this field will be to see if there are other strategies or combinations where we can incorporate PARP inhibitors. New-generation PARP inhibitors are currently under study that specifically inhibit PARP1, which can lead to less myelosuppression and might be more easily combined with other agents like chemotherapies or other myelosuppressive drugs, including drugs that target other DNA repair pathways like ATR. Understanding the populations that are likely to benefit, [determining] biomarkers that might predict that benefit, [and developing] newer drugs and combinations is all exciting.

What biomarkers may predict PARP inhibitor benefit in patients with mCRPC?

The greatest benefit from PARP inhibitors is in patients with BRCA2 gene alterations. The degree of benefit across all other HRR gene alterations is varied, and some gene alterations don’t seem to benefit at all. [However, there may be] other strategies to target the DNA damage repair pathway, even in patients without BRCA2 gene alterations. Combinations or newer agents targeting other members of that pathway are probably where that research will go. However, it’s still too early to understand how we can better treat the patients without HRR gene alterations.

What main message would you like colleagues to know about PARP inhibitors in this population?

The greatest benefit of using PARP inhibitors as monotherapy is in patients with BRCA2 gene alterations, and likely [those with] BRCA1 alterations as well. [The benefit in patients with] a mutation in ATM, CHEK2, or CDK12 is likely to be quite modest, based on the information we have so far. [Patients with mutations in] other genes that are more canonically involved in HRR, like PALB2, RAD51, and FANCA, might benefit, but we need much more data around that. 

Olaparib in combination with abiraterone acetate is not yet approved by the FDA, though it is approved in the European Union. If it becomes approved in the US, the context in which it would probably be most helpful is in patients who have not been previously treated with potent hormonal agents. [This combination may be most beneficial in the] first line [in patients with] mCRPC who have a known BRCA2 mutation or other known HRR deficiency mutation. [If those patients] have relatively high-burden disease and you want to cytoreduce them quickly, you could certainly use that combination. However, anything outside of that clinical context is difficult to justify based on existing data. That’s why we need further study of these combinations moving forward.

References

1. De Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
2. Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(suppl 6):12. doi:10.1200/JCO.2022.40.6_suppl.012