PARP Inhibitors Play Key Role in Prostate Cancer Paradigm, as Hunt for Biomarkers Continues

The FDA approvals of the PARP inhibitors rucaparib (Rubraca) and olaparib (Lynparza) have expanded options for patients with prostate cancer who harbor certain mutations, according to Wassim Abida, MD, PhD, who added that research efforts are now focused on exploring differences in sensitivity to these agents in relation to the mutations that are present, identifying effective biomarkers of response, and overcoming resistance.

“It is important for [us, as well as our] patients to understand the likelihood of response, which could be very low, if a mutation is present in [certain] genes,” Abida said. “All these genes are different, and we need to learn more about them, and about how best to target tumors that [harbor them].”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on prostate cancer, Abida, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the role of PARP inhibition in the treatment of patients with prostate cancer, and the importance of biomarkers in guiding treatment decisions with these agents.

OncLive^®: What were the key lessons learned from the TRITON2 study (NCT02952534)? How have these data impacted the prostate cancer treatment landscape?

Abida: TRITON2 was a monotherapy study of the PARP inhibitor rucaparib in patients with advanced prostate cancer who had [previously received treatment with] an androgen receptor [AR]–directed therapy, as well as 1 line of taxane-based chemotherapy. All patients must have had a mutation, [which included] 1 of several genes, but the key group [examined were] those [whose tumors harbored] BRCA1/2 mutations. Patients were assessed for radiographic response rate as the primary end point, as well as prostate-specific antigen response rate, time on treatment, and other factors as secondary end points.

The key finding from that study was that men who had BRCA1/2 mutations achieved high rates of radiographic response to rucaparib monotherapy, approximately in the 45% to 50% range. That led to the approval of the agent for use in men with BRCA1/2 mutations who had received AR-directed therapy and taxane-based chemotherapy.

How did TRITON2 differ from the PROfound study (NCT02987543)?

PROfound and TRITON2 differ in [study type], scale, and context of use. PROfound is a randomized phase 3 trial comparing olaparib [Lynparza], another PARP inhibitor, with physician’s choice of a second-line AR-directed therapy. PROfound also did not require a prior line of taxane-based chemotherapy; it had a mixed patient populion, from that perspective. 

The primary end point [of the trial] was a progression-free survival. However, it was not limited to [those with] BRCA1/2 [mutations]; it included [those with] ATM [mutations]. Additionally, the study included a second cohort [of patients with] an additional genes [beyond] BRCA1/2 and ATM.

In the final analysis, all the genes were included except for 1. The main difference was that olaparib ended up being approved for more than just [patients with] BRCA1/2-mutant metastatic castration-resistant prostate cancer.

What are the limitations associated with PARP inhibition in prostate cancer?

The limitations come down to which genes may be sensitizing biomarkers to PARP inhibitors. That is one of the key differences between the TRITON2 and PROfound studies. [TRITON2] focused on patients with BRCA1/2 mutations, and the strongest responses [were seen in patients with] BRCA2-mutated disease. PROfound included [patients with] a total of 13 genes, and led to the approval of olaparib for those 13 gene mutations. However, when you look at the details in terms of response rate by gene, it is clear that some genes do not look like they sensitize to PARP inhibitors.

Are any ongoing or planned studies further examining biomarkers of response to PARP inhibitors in this population?

There definitely are. Different studies are using different classes of agents that target specific alterations in these genes. For example, more than 2 studies are examining the use of ATR inhibition to target tumors that have ATM mutations, which, based on the current PARP inhibitor studies, do not [seem to] sensitize to PARP inhibitor therapy. [Other] studies are seeking to target CDK12 mutations in advanced prostate cancer using immunotherapy and other agents.

Those are the 2 key [studies to watch for], because those are the most common [mutations observed in this patient population] after BRCA2. Additional studies are being planned [to examine these agents in those with] other, less commonly altered genes.

If a patient does not have a BRCA1/2 mutation, but has one of the 10 mutations that were included on PROfound, are you likely to recommend a PARP inhibitor?

It depends on the gene. Some infrequently altered genes are highly related in function to BRCA, and preliminary data suggest, based on small numbers, that they do sensitize to PARP inhibitors. [Such mutations include] PALB2 and BRIP1. In TRITON2m there was a cohort of non-BRCA genes [in whom] we saw responses. PROfound showed [responses in those with these mutations, as well]; therefore, I would [utilize a] PARP inhibitor [in these patients]. However, for a patient with a CDK12 or an ATM mutation, I am not convinced there is clinical benefit [with this approach] based on the data [reported thus far], and would direct [these patients] toward a clinical trial.

For patients who are eligible to receive either rucaparib or olaparib, what factors do you consider when selecting between them?

[If a patient has a] BRCA2 mutation, they are eligible to receive both agents. The toxicities [with the 2 drugs] are similar, and the decision often comes down to clinician choice and comfort with the agent. The main adverse effects [AEs] of both appear to be similar, [and include] fatigue and nausea, although they are generally tolerable. Anemia [is another common AE] that appears to occur at similar rates for both agents, and often shortly after the initiation of the study drug. This [toxicity] occasionally requires a blood transfusion, but typically it stabilizes and is tolerable.

Looking forward, what are some key areas of unmet need that research efforts should focus to address?

One of the main [areas we need to focus on] are biomarkers. Although strong prospective studies have led to FDA approvals for PARP inhibitors, [biomarkers of response to these agents] can still be improved. For example, [patients with] BRCA2-mutations respond at a rate of approximately 50% [to these drugs], but that means that half of patients with BRCA2 mutations do not respond. [We must] refine biomarkers, [using technologies like] signature analysis.

Another concern is resistance in patients who either do not respond up front, or who develop resistance after responding initially. How do we target resistance? What are the mechanisms of resistance? More insight is needed. In order to target [this] better, we need to understand this better.