PARP Inhibitors Pave Way for Personalized Care in CRPC

Earle F. Burgess, MD

The emergence of effective PARP inhibitors like olaparib (Lynparza) and rucaparib (Rubraca) in the metastatic castration-resistant prostate cancer (CRPC) paradigm represents a shift away from a one-size-fits-all approach toward a more personalized treatment, according to Earle F. Burgess, MD, who added that the choice between these agents will be largely dependent on molecular data, overall disease burden, and performance status.

Results of phase 3 PROfound trial (NCT02987543) showed that olaparib reduced the risk of disease progression or death vs abiraterone acetate (Zytiga) or enzalutamide (Xtandi; HR, 0.49; 95% CI, 0.38-0.63; P <.0001).1 These data led to the May 2020 FDA approval of the PARP inhibitor for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC who progressed following prior antiandrogen agents.

Rucaparib was shown to have a confirmed objective response rate of 43.9% in patients with BRCA1/2-mutated CRPC, with a 52.0% prostate-specific antigen response at a median follow-up of 13.1 months, according to findings from phase 2 TRITON2 trial (NCT02952534).2Results from this trial led to the accelerated approval of the agent in May 2020 for patients with metastatic CRPC harboring a BRCA mutation who had received androgen receptor–directed therapy and taxane-based chemotherapy.

“In terms of the probable efficacy of these agents, it is important to consider factors like clinical characteristics, underlying mutations, and relative probability of response,” Burges said. “…It is important to consider what other remaining agents are available to that patient, their overall disease burden, and performance status.”

In an interview with OncLive^® during a 2021 Institutional Perspectives in Cancer webinar on prostate cancer, Burgess, Burgess, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discussed optimizing the use of PARP inhibitors in the treatment of patients with advanced prostate cancer.

OncLive^®: In the PROfound trial, how did olaparib perform across the different subgroups of patients enrolled?

Burgess: PROfound was a randomized phase 3 trial that established that olaparib, a PARP inhibitor, has efficacy in patients with metastatic CRPC that have been previously treated with either enzalutamide [Xtandi] or abiraterone [Zytiga]. On this trial, patients were randomized 2:1 to receive either olaparib or retreatment with enzalutamide or abiraterone. To be included in the study, there was requirement for either a germline or somatic mutation in a panel of 15 genes that are involved with HRR. There were 2 separate molecularly-defined cohorts. Cohort A included patients with BRCA1, BRCA2, or ATM mutations, and cohort B included 13 additional genes that are involved in HRR.

Although the study itself was not powered to interrogate the efficacy of olaparib at the individual gene level, a few things were evident. One was that the patients included in cohort A appeared to derive greater benefit with olaparib than those in cohort B. At the individual gene level, the study was not designed to interrogate that question, but from the data that we have available, it is evident that there is variable sensitivity across the individual genes to olaparib. For example, patients who had the most prevalent mutation, which was BRCA2, appeared to fare better than those with other prevalent [mutations like] ATM.

The take-home point when following the current labeled indication for the drug, which includes 14 of the genes on the study, is that clinicians should not apply a one-size-fits-all mindset; they should expect that patients may have variable sensitivity to the drug based on their underlying genetic or genomic mutation. That should influence the practitioner’s threshold in terms of how long they may be willing to treat the patient.

Could you speak to the significance of the TRITON2 trial with rucaparib?

TRITON2 is a single-arm, multicohort, phase 2 trial that led to the accelerated indication for rucaparib as monotherapy for patients with advanced CRPC. [This trial] differs a little bit from the design of PROfound in that the current label for rucaparib requires patients to fill both the next-generation endocrine agent abiraterone or enzalutamide plus docetaxel. The eligible genomic mutations are also more restrictive in that it rucaparib currently only allows for patients with BRCA1 and BRCA2 mutations. [Results] showed that rucaparib has robust activity in patients with a BRCA1 or BRCA2 mutation in whom prior docetaxel and the next-generation endocrine agent had failed. The confirmatory phase 3 TRITON3 [NCT02975934] trial is currently ongoing.

How have the approvals of olaparib and rucaparib impacted the paradigm?

The approval of olaparib and the accelerated approval of rucaparib in the advanced castrate-resistant space were important additions to the armamentarium of agents that we have available for patients with advanced prostate cancer, particularly in the 25% of patients who have underlying germline or somatic aberrations, and HRR genes. Based on the efficacy of these agents, it is evident that many patients with these aberrations benefit. In addition, the availability of PARP inhibitors for these patients are a nice option because they are oral agents and, for most patients, the overall toxicity profile is superior to that of taxane-based chemotherapy.

How do you choose between olaparib and rucaparib in practice?

There are factors to consider when identifying patients who may be eligible for a PARP inhibitor just on the basis of their molecular findings, either a germline or somatic gene aberration, that would qualify them at current labels. It is important to understand from the efficacy data that the individual gene mutations may not have equal efficacy. Specifically, patients with BRCA2 aberrations, from what we can tell, probably have a better likelihood of benefiting from a PARP inhibitor than those with ATM mutations. Considering there is likely to be variable efficacy across the different genes, that is important [to consider] when trying to decide when to use these agents and in whom in a routine clinical setting.

For example, if I have a patient who has a high burden of symptomatic metastatic disease, where it is important to achieve a response, which gene defect the patient has that qualifies them for a PARP inhibitor is going to influence when and how I use the agent. If I have a patient with a BRCA2 mutation who I believe to have a higher likelihood of responding to a PARP inhibitor than [someone with an] ATM mutation, and they have a high burden of symptomatic disease, then I am inclined to use a PARP inhibitor in that setting. If it is the same patient, however, with an ATM mutation, I am going to be more concerned that they may not respond. If I have other agents, other classes, that have efficacy, such as taxane chemotherapy, and the patients chooses the other agent in lieu of the PARP inhibitor, then the more symptomatic patient with a mutation that I am more concerned about may not respond.

The inverse is true, as well. If it is a patient with a mutation, for example, ATM again, that I have concern may not be as likely to respond but has a very low burden of disease, or is asymptomatic, I am more inclined to utilize the PARP in that setting knowing that if the agent does not work, that I am not going to lose clinical control of the patient. This is most commonly the discussion that I will have with patients who are seeking to delay when they may use a taxane, for example.