Evolving Use of PARP Inhibitors Requires Biomarker-Driven Approaches for Treatment Selection in Prostate Cancer

As the role of PARP inhibitors both alone and in combination with androgen receptor signaling inhibitors (ARSIs) continues to evolve within prostate cancer, attention to patient factors, mutational status, and prior therapies received is vital for maximizing the well-documented efficacy of this drug class, according to Vivek K. Narayan, MD, MS, who noted that research is still needed to elucidate the sequencing of these therapies for patients with progressive castration-sensitive disease.

“...The preponderance of evidence indicates that the vast benefit of PARP inhibitors in the castration-resistant setting, by and large, is dependent on the mutation that is present,” Narayan said in an interview with OncLive^® following a State of the Science Summit^™ on bladder and prostate cancer, which he chaired.

In the interview, Narayan spotlighted 3 case studies of patients with metastatic prostate cancer, delving into the influence of their unique mutational status on treatment decision-making, scenarios in which to utilize PARP inhibitor monotherapy vs combination regimens, and key trials that support the use of each approach.

Narayan also expanded on key topics across genitourinary cancers that were discussed by his colleagues, who are affiliated with Penn Medicine, Fox Chase Cancer Center, and Sidney Kimmel Cancer Center at Jefferson Health. This included key factors influencing treatment navigation in metastatic urothelial cancer; data supporting current treatment strategies, sequencing, and investigations of bladder preservation in muscle-invasive bladder cancer (MIBC); the optimal application of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC); and the optimal use of combination therapy with ARSIs and PARP inhibitors in prostate cancer.

Narayan is an assistant professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania in Philadelphia.

OncLive: Could you briefly outline the 3 patient cases featured in your case discussion on PARP inhibitors in prostate cancer, detailing how each patient’s disease presented and how clinicians proceeded with treatment?

Narayan: I presented 3 individual patient cases to highlight some of the evolving thought around the use of PARP inhibitors in patients with advanced prostate cancer. The first case was a patient who had progression of mCRPC after standard treatment with chemotherapy and ARSIs, such as abiraterone acetate [Zytiga] or enzalutamide [Xtandi]. This is a patient with a known underlying pathogenic BRCA2 mutation. In this case, the idea was to highlight PARP inhibitors such as olaparib [Lynparza], which have already gained regulatory approval in this particular treatment space as well as highlight the biomarker-driven nature of the use of these therapies. All the panelists essentially agreed with the use of a PARP inhibitor in that clinical setting, knowing that we have level 1 evidence for use of PARP inhibitors in those treatment-exposed patients with known biomarkers such as a BRCA2 [mutation].

The second treatment case highlighted some of the more recent data that we've seen from studies such as the [phase 3] PROpel study [NCT03732820], or more recently from the [phase 3] TALAPRO-2 [NCT03395197] trial. This [trial was conducted] in patients who have not yet received ARSIs, so we are looking at the first-line mCRPC setting. Again, the patient had an underlying pathogenic BRCA mutation. This was meant to highlight the use of ARSI therapies, such as abiraterone in combination with olaparib, [which showed] clinical benefit in the PROpel data, or enzalutamide in combination with talozoparib [Talzenna] as we saw in TALAPRO-2. We highlighted [this example] to show that these agents can be used in patients progressing on androgen deprivation therapy [ADT] alone in the first-line mCRPC setting. The use of PARP inhibitors in combination with novel anti-androgen therapy such as enzalutamide or abiraterone shows clear clinical benefit in that biomarker-driven population.

The third clinical case is where things entered a more data-free zone, and it was interesting to see the varying thoughts from the panelists in the discussion. This case reflects contemporary clinical practice, but we don't yet have level 1 evidence to truly inform the optimal use of PARP inhibitors. This patient had de novo mCSPC and was treated with a contemporary regimen of ADT and an ARSI such as abiraterone in the castration-sensitive setting. At the time of progression, especially in the setting of a known pathogenic BRCA2 mutation, the question becomes: what do we use as the optimal next therapy? The different options that the panelists put forth was switching to a PARP inhibitor monotherapy. This was based on data from studies like the [phase 3] PROfound study [NCT02987543], which showed that PARP inhibitors can be used and already have regulatory approval in the castration-resistant setting as monotherapy after progression on an ARSI. [Another option] would be to potentially utilize PARP inhibitors in combination with alternative ARSI therapies, which could also be extrapolated from studies like PROpel and TALAPRO-2. We saw a lot of understandable variation in treatment use among the various panelists. This speaks to some of the evolving use of PARP inhibitors, and the unanswered questions that we have despite the TALAPRO-2 and PROpel data.

Based on these case studies, what factors could help inform the use of PARP inhibitors post-ARSI therapy compared with their use in the first line following treatment with ADT?

The panelists very nicely highlighted how they may make these treatment decisions. First and foremost are clinical factors that we think about in terms of the pace of the disease, whether a patient may be progressing with just a rising prostate specific antigen [PSA] level, or whether there is more symptomatic or radiographic evidence of disease progression. In other words, we're thinking about how to judge the tradeoff between balancing quality of life and adverse effects from a next-line systemic therapy vs its anticipated efficacy based on the clinical setting that we're dealing with. For example, if a patient was having just a rising PSA on an agent like abiraterone alone, some of the panelists advocated for adding a PARP inhibitor, as opposed to sort of a more significant change in their systemic therapy approach. These are clinical scenarios where we don't have [sufficient] level 1 phase 3 trial data to best answer this question. However, it speaks to some of the clinical factors that providers think about when making these decisions on an individual patient basis.

Given the complexity of results from trials involving combination ARSI-PARP inhibitor therapy in the frontline for patients with mCRPC, as presented by Samuel Takvorian, MD, MS, how do you interpret these data?In what patient populations does this approach seem most effective?

Most of the data are showing that the benefit [with PARP inhibitor combinations] is largely seen in patients who harbor some homologous recombination DNA repair defect [HRD], as we saw in the TALAPRO-2 data. When we narrow it further to patients who are harboring a pathogenic BRCA1/2 mutation, different trials [have shown] that these patients appear to drive the clinical benefit seen with PARP inhibitors in combination with ARSIs. In my practice, those are the patients that we need to identify [and administer] PARP inhibitors to early in the clinical treatment paradigm, in order to achieve the best and most significant clinical benefit.

With recent data supporting the use of treatment intensification as a new standard of care in mCSPC, what future developments still need to occur to maximize the clinical benefit of this approach, as per the presentation by Kevin Kayvan Zarrabi, MD, MS, FACP?

Dr Zarrabi gave a nice overview of the concept of treatment intensification both with the use of ARSIs in mCSPC but also with this concept of triplet therapy with ARSIs, ADT, and taxane chemotherapy as an initial treatment intensification approach. As he showed, the data for this triplet combination appears to be greatest in those with high-volume, de novo metastatic presentations, although there may be other clinical subgroups that derive some benefit from this overall triplet intensification. With this use of upfront intensification, we're seeing significant improvements in long-term clinical outcomes across the different prognostic risk groups in metastatic prostate cancer. Some of the remaining questions are: who derives the greatest benefit from incorporating chemotherapy into upfront treatment intensification? Is it purely [influenced by] clinical factors, [as seen in] those patients with de novo, high-burden metastatic presentations? Are there potentially biomarkers that we could incorporate to help us with this treatment decision making? Are there some patients who we can get away with ADT and an ARSI [without the] potential toxicity of chemotherapy in an upfront intensification approach?

The other clinical question that will come up in practice as we are giving more intensified initial treatment regimens, and hopefully achieving better long-term clinical outcomes, is [whether] there are potential patients for whom we can ultimately de-intensify therapy in order to better balance both long-term clinical efficacy and the known cumulative toxicities that can occur with long-term exposure to these hormonally-driven agents. These clinical questions remain [unanswered], but hopefully we'll see some new study designs and data in the coming years [to address them].

Shifting focus, how does real-world evidence influence or reinforce the current sequencing of platinum chemotherapy vs immunotherapy-based regimens in MIBC, according to Ronac Mamtani, MD MSCE?

Dr Mamtani highlighted evolving data on the sequencing of therapies for patients with metastatic urothelial cancer. He showed some real-world data [illustrating] how, even after level 1 evidence, the uptake of novel therapies can often be relatively slow in metastatic urothelial cancer. He showed data with the use of maintenance avelumab [Bavencio] after platinum-based chemotherapy and showed similar data with the use of FGFR inhibitors in patients with later-stage metastatic urothelial cancer harboring relevant alterations. One takeaway is that, as we're seeing the treatment paradigm evolve for the management of metastatic urothelial cancer, we'll have to also think about how to appropriately disseminate this information and make sure level 1 evidence is being incorporated in contemporary practice.

Based on the case discussion facilitated by Jason E. Shpilsky, MD, what were some of the key decision points in metastatic urothelial cancer, and what unanswered questions remain regarding current treatment approaches for this population?

Dr Shpilsky highlighted the factors that we use in clinical decision-making when choosing different regimens in the treatment of [patients with] metastatic urothelial cancer. This is particularly relevant because, as we've seen with recent data and recent press releases, we anticipate that the number of options for patients with metastatic urothelial cancer is going to expand. Enfortumab vedotin-ejfv [Padcev] and pembrolizumab [Keytruda] [may] move earlier into the metastatic or untreated clinical space, [and we have] recent press releases about nivolumab [Opdivo] in combination with cisplatin-based chemotherapy potentially [being used] in the frontline setting for [patients with] metastatic urothelial cancer. As we have all these different regimens, and they have different potential benefits and toxicity profiles, how will we make these decisions, especially in the untreated or first-line metastatic urothelial cancer space? It's becoming a bit more complex than just thinking about whether a patient is cisplatin eligible or ineligible.

What emerging approaches to bladder preservation are showing promise in localized MIBC according to data presented by Pooja Ghatalia, MD?

Dr Ghatalia's presentation was particularly interesting, as it highlighted some of the innovative strategies that her group and others are looking at in the realm of MIBC, [including] the potential role for bladder-preserving strategies. They're doing some innovative work looking at neoadjuvant therapies and how we can potentially incorporate some of the more highly-active therapies into the neoadjuvant setting. Importantly, [they're] integrating biomarkers into those studies to better understand if there [are circumstances in which we could] potentially preserve the bladder and avoid cystectomy in patients who have had excellent responses to neoadjuvant therapy. It's a fascinating clinical question, and a lot of work is being done in this space. I look forward to more results as they become available.

Please spotlight any planned or ongoing trials in the prostate cancer space that are being conducted at your institution.

[At the University of Pennsylvania], we are currently conducting several trials to see how PARP inhibitors could be optimally used in the treatment of [patients with] advanced prostate cancer. These generally fall into two categories. The first category is clinical trials [investigating] ways of utilizing PARP inhibitors in mCRPC. One example of this is an ongoing, investigator-initiated clinical trial [aiming] to extrapolate an approach that's used in ovarian cancer, breast cancer, and pancreatic cancer for patients who harbor pathogenic BRCA1/2 mutations and apply it to patients with mCRPC. This is the concept of PARP inhibitor maintenance after patients have received platinum-based chemotherapy for their disease. This [approach is] routinely done in some other solid tumors, and we're trying to apply it to patients with prostate cancer who have a known pathogenic BRCA1/2 mutation [and have been treated with] platinum-based chemotherapy. Following some initial treatment response to platinum-based chemotherapy, we readily put patients directly onto a maintenance PARP inhibitor, which is niraparib [Zejula] in this case. The idea is to extend that initial treatment response to platinum-based chemotherapy in a more tolerable way without the cumulative exposure to long-term chemotherapy. That's an ongoing clinical trial in mCRPC.

The other category of [studies] trying to better understand the use of PARP inhibitors is in the castration-sensitive setting. There's a number of ongoing and planned phase 3 clinical trials trying to see if we can bring PARP inhibitors into earlier treatment settings, particularly in those patients with BRCA1/2 or other HRD mutations, to see if that can lead to better long-term clinical benefit.