Consensus Guidelines Needed to Further Optimize PARP Inhibition, Molecular Imaging, and ARPI Use in Prostate Cancer Management

Despite recent advancements with PARP inhibitors, prostate-specific membrane antigen (PSMA) PET/CT imaging, and earlier use of androgen receptor pathway inhibitors (ARPIs), significant gaps in evidence and a lack of clear clinical guidance continue to create uncertainty in the management of advanced prostate cancer, underscoring the need for consensus recommendations to inform treatment decisions across a heterogeneous disease landscape, according to Rana R. McKay, MD.

McKay and colleagues delved into ongoing innovations as well as critical diagnostic and therapeutic gaps in the management of prostate cancer at the 2025 Bridging the Gaps in Prostate Cancer consensus meeting. Following the meeting, a consensus manuscript outlining such developments, expert treatment recommendations, and other emerging considerations for disease management is compiled.

“The meeting was designed to bring individuals together to address those controversial areas where there is a lack of level 1 evidence to guide decision-making,” explained McKay, a professor in the Departments of Medicine and Urology at the University of California (UC) San Diego School of Medicine, as well as a medical oncologist with UC San Diego Health. “This work is critically important because it helps clinicians and practitioners better manage and treat their patients in the clinic.”

In an interview with OncLive®, McKay expanded on the importance of the Bridging the Gaps in Prostate Cancer meeting, and provided additional insights on the utility of PSMA PET/CT scans for patients with biochemical recurrence; challenges and advancements in the use of PARP inhibitors and novel therapies in advanced prostate cancer; and ongoing clinical trials aiming to improve treatment outcomes for advanced prostate cancer.

OncLive: What is the importance of publishing this manuscript?

McKay: The meeting was convened to bring together key opinion leaders to dive into the areas where there is a lack of level 1 evidence on how to manage patients with prostate cancer. There are many areas in clinical practice where a clinician is treating a patient in front of them, and there is no clear guidance from the guidelines on exactly what to do. As a result, there is a lot of variability in clinical decisions around imaging and therapeutics.

How has the evolving use of PSMA-PET and CT scans helped improve the management of biochemically recurrent disease?

PSMA PET/CT represents a paradigm shift in managing biochemically recurrent disease, and it has dramatically improved our ability to detect and localize disease at much lower levels of PSA than conventional imaging. This enhanced sensitivity of detecting lesions at PSA levels often below 1 has fundamentally changed our treatment approach by enabling earlier, more targeted interventions.

The expanded treatment landscape includes several key areas. First, it enables precision salvage radiotherapy by more accurately identifying oligometastatic disease, allowing for stereotactic approaches that can target specific lesions rather than empiric, whole-pelvis radiation. Second, it better informs decisions about systemic therapy timing and selection. It also opens up opportunities for targeted treatments.

However, it has also created a lot of uncertainty, because we are seeing stage migration; patients are now diagnosed with metastatic disease at a time when they would not have been previously. That also presents a controversy in the field.

What are some key considerations for treatment selection in metastatic castration-sensitive prostate cancer (mCSPC)?

Treatment selection for mCSPC requires careful consideration of multiple patient and disease factors. The key considerations that help strategize around what to do include disease volume and distribution, specifically distinguishing between high-volume and low-volume disease, as well as the presence of visceral metastases and the extent of bone metastases. This can impact prognosis and, in some scenarios, may also impact treatment selection.

Other factors, like age, performance status, comorbidities, and life expectancy, are also important to consider. Sometimes we think about genomic factors as well. mCSPC is a grossly undertreated disease. We've demonstrated across the spectrum that patients do have improved outcomes when they receive hormonal therapy with an escalated ARPI. However, we know that in clinical practice, approximately one-third of patients are still receiving therapy with androgen deprivation therapy [ADT] alone. There's a lot of opportunity to improve upon that.

We've also demonstrated that the combination of ADT, ARI, plus chemotherapy improves outcomes, but the rates of triplet therapy utilization are [approximately] 10% to 15% in the United States [US]. There’s a lot of opportunity to improve outcomes for patients in this context. Additionally, prostate radiotherapy can also be considered for individuals who present with de novo low-volume disease, and [some] data suggest that this is associated with improved outcomes.

The treatment landscape for mCSPC has dramatically changed, and this requires a lot of consideration about various factors when selecting exactly what to do for any given patient.

Despite advancements with PARP inhibitors in prostate cancer, what are some challenges that may limit their implementation in clinical practice?

There are several challenges that limit the optimal PARP inhibitor implementation. The primary challenge is actually the identification of patients through comprehensive genomic testing who may be eligible for PARP inhibitors. Although we've seen an uptick in both germline and somatic tumor profiling, many patients still do not receive this testing, even though they have advanced disease. There's a lack of streamlined pathways for setting up this testing. Some centers do it well; others lack the resources and the infrastructure. If you don't test, at least in the US, there’s no indication for a PARP inhibitor unless you know that somebody has an underlying HR gene alteration.

Additionally, there's complexity in interpreting the genetic testing results and understanding the implications for family members. Sometimes, there may be a need for specialized genetic counseling, and we know there's a gross shortage of genetic counselors across the US, as genetic and germline testing has really expanded.

Practical implementation challenges also include toxicity management, particularly around the hematologic profile, and drug-drug interactions, which require careful attention.

In which patients would you consider the use of lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) in metastatic hormone-sensitive prostate cancer (mHSPC)?

Patient selection for lutetium Lu 177 vipivotide tetraxetanrequires careful evaluation across multiple dimensions. We've seen this agent initially approved for patients in the post-androgen receptor pathway, post-taxane setting with late-line disease that is PSMA-positive, and now move into the pre-taxane setting. We also recently heard in a press release that the [phase 3] PSMAddition Trial [NCT04720157] was positive, which is testing this agent in the metastatic hormone-sensitive prostate cancer setting.

Candidates must have PSMA-positive disease confirmed by appropriate imaging, and they need to have progressed through, at this time, at least an ARPI and, historically, chemotherapy. However, now the label has been expanded into the pre-chemotherapy space. Importantly, clinicians need to assess the imaging to confirm that patients have PSMA-positive disease as opposed to PSMA-negative disease, as those patients are not candidates. There are criteria around that, based on the [phase 3] VISION trial [NCT03511664] with uptake above the background of the liver.

The big consideration in the clinic is determining how best to sequence this therapy; when to implement it, whether pre-chemotherapy or post-chemotherapy, and after which lines of therapy. Managing the toxicity profile is also important, including monitoring for marrow suppression, renal toxicity, salivary gland toxicity, and long-term toxicity. These are some of the critical considerations for selecting, sequencing, and monitoring this therapeutic.

What is the significance of moving ARPIs in earlier lines of therapy for metastatic prostate cancer, and how does this increase the benefit of novel therapies?

Moving ARPIs to earlier treatment lines represents a fundamental shift toward more aggressive upfront treatment for patients with metastatic prostate cancer. This shift began in 2015 with the results of the [phase 3] CHAARTED [NCT00309985] and STAMPEDE [NCT00268476] trials. Since that time, these agents have been moved earlier and earlier in the treatment paradigm. Additional data from STAMPEDE in patients with high-risk, localized, non-metastatic disease demonstrated benefits with the addition of abiraterone. We also saw data from the [phase 3] EMBARK study [NCT02319837] for high-risk biochemical disease that demonstrated benefit with the addition of enzalutamide [Xtandi]. So across multiple spectrums and high-risk populations, we are seeing the benefit of these agents.

The significance lies in treating the disease when it is most hormone sensitive, before the development of resistance mechanisms that make later treatment less effective. This strategy increases the benefits of novel therapies in several ways and potentially prolongs the castration-sensitive phase of the disease—during which patients have better quality of life, fewer symptoms, and delayed emergence of aggressive, treatment-resistant disease—by maintaining more complete androgen suppression from the onset.

We have seen a number of novel treatments being developed in the metastatic castration-resistant disease setting that are very exciting. These include antibody-drug conjugates, particularly those targeting B7-H3, as well as next-generation hormonal agents, including CYP11 inhibitors. Androgen receptor degraders are also being tested. Additionally, we have seen exciting data around bispecific agents—specifically the CD3 bispecifics targeting KLK2. There are many promising therapeutics being developed in the advanced setting and moving across the treatment landscape.

What are some ongoing clinical trials to keep an eye on in the prostate cancer space?

One of the first studies [of interest] is being conducted in the metastatic castration-resistant setting. It’s a study called PREDICT, which uses both DNA and RNA sequencing for arm allocation for patients. It’s a platform study and based on the underlying genomic profile of the tumor, patients are allocated into a designated treatment arm. This study is being conducted through the Alliance Cooperative Group. It’s currently open and actively enrolling patients. There’s an arm specifically targeting aggressive variant prostate cancer: those that have Rb loss, neuroendocrine differentiation, or a neuroendocrine signature. There’s a taxane and platinum sensitivity arm, and then a biomarker-negative arm. The platform of the trial is also looking to expand.

Additionally, there’s another [phase 3] trial currently in development that we anticipate will open before the end of the year. It’s a study called ASPIRE [NCT06931340]. It’s being conducted in the mHSPC setting and is testing the addition of docetaxel to the backbone of ADT plus apalutamide [Erleada].

I’m super excited about these trials, which are certainly going to help provide important information about therapeutics for patients with advanced prostate cancer.