New Options Poised to Make a Splash in Metastatic Prostate Cancer

Matthew Rettig, MD

Although patients with stage IV metastatic prostate cancer historically have a 5-year overall survival (OS) rate of approximately 28%, new treatment options have emerged in the arsenal for clinicians tasked with managing these patients in an effort to improve these rates.¹

In an interview with OncLive^®, Matthew Rettig, MD, chief of hematology-oncology at the VA Medical Center in Greater Los Angeles, and a professor of medicine and urology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), discussed this and other related topics during the Inaugural Prostate Cancer Conference, hosted by OncLive^®.

In the interview, Rettig touched on a couple of intriguing trials in metastatic prostate cancer that were discussed during the conference, including the phase 3 ARASENS study (NCT02799602). ARASENS randomly assigned patients with metastatic hormone-sensitive prostate cancer to receive either darolutamide (Nubeqa) at 600 mg twice daily (n = 651) or placebo (n = 655). The primary end point of the study was OS.²

Findings from the trial showed that at the October 25, 2021, primary analysis data cutoff, there was a 32% reduction in the risk of death in the investigational arm vs the control arm (HR, 0.68; 95% CI, 0.57-0.80; P < .0001). Additionally, at a median follow-up for survival at 43.7 months and 42.4 months in the darolutamide and control arms, respectively. The median OS was not reached (NR) in the darolutamide arm compared with 48.9 months (95% CI, 44.4-NR) in the placebo arm (HR).

In a subgroup analysis of the ARASENS trial, which was presented during the 2023 Genitourinary Cancers Symposium, the survival benefit with darolutamide was observed across prespecified subgroups, such as high- and low-volume disease and high and low-risk disease. Among patients with high-volume, metastatic hormone-sensitive prostate cancer who received darolutamide, the median OS was NR (95% CI, 50.3-NR) vs 42.4 months (95% CI, 39.7-46.0) for those treated with placebo (HR, 0.69; 95% CI, 0.57-0.82).³ Additionally, patients with low-volume disease had a median OS of NR (95% CI, NR-NR) and NR (95% CI, NR-NR), respectively (HR, 0.68; 95% CI, 0.41-1.13). High-volume disease was defined as visceral metastases and/or at least 4 bone metastases with at least 1 beyond the vertebral column/pelvis.

Those with high-risk disease experienced a median OS of NR (95% CI, NR-NR) compared with 43.2 months (95% CI, 40.0-48.9) when treated with darolutamide vs placebo, respectively (HR, 0.71; 95% CI, 0.58-0.86). In the low-risk subgroup, the median OS was NR (95% CI, NR-NR) in both arms (HR, 0.62; 95% CI, 0.42-0.90). High-risk disease was defined as displaying at least 2 risk factors: Gleason score of at least 8; at least 3 bone lesions; and/or presence of measurable visceral metastases.

Rettig discussed these findings and other data sets in more detail during the interview. He also briefly offered his perspective on other clinical trial data presented during the 2023 Genitourinary Cancers Symposium, which was held February 17-19, 2023, in San Francisco, California.

OncLive^®: Of the sessions that you participated in during the Inaugural Prostate Cancer Conference, which did you feel were most important and why?

Rettig: There were a number of different interesting conversations. A lot of the focus was on areas that were controversial, and that was the intent of the discussion. A couple of areas [of interest] were treatment intensification in the metastatic castration-sensitive prostate cancer space, and the role of molecular imaging—specifically prostate-specific membrane antigen PET CT scans—in the management of prostate cancer.

Specific to the session concerning metastatic hormone-sensitive prostate cancer, what were the key elements of this discussion?

For decades, the backbone of therapy for advanced metastatic prostate cancer in the hormone-sensitive setting has been androgen deprivation therapy [ADT] only. Starting about 7 or 8 years ago, we learned that adding therapy to that backbone of ADT, [with] that second agent being chemotherapy with a taxane or a second novel hormonal agent, markedly improved survival much more so than reserving those same agents for the metastatic castration-resistant space.

There was a lot of discussion about second-generation agents and what specific patient populations could benefit [from them]. One of the highlights of the discussion was about 3 drugs potentially being better than 2. There are data that have come out [from the 2023 Genitourinary Cancers Symposium] of a subgroup analysis of the] ARASENS study that demonstrated the utilization of 3 drugs consisting of ADT, docetaxel, and the novel hormone-signaling agent darolutamide improves overall survival [OS] irrespective of the subgroup. Whether the patients had high-volume prostate cancer, low-volume recurrent prostate cancer, or de novo disease, it seemed that there was a benefit across all subgroups.

But there was a lot of discussion about whether patients who didn't have the adverse prognostic features such as low-volume disease or recurrent disease, which are more favorable features, whether or not they needed the 3-drug regimen, and if a 2-drug regimen—just using a hormonal-signaling agent—would be sufficient. There was a lot of back and forth there and there are some unsettled questions.

[Another intriguing topic is] the role of molecular imaging. Molecular imaging is changing how we visualize cancer in multiple states of the disease: when patients are initially diagnosed, when they have a first recurrence, [and] when they transition into castration-resistant disease. How do we interpret those scans? How do we apply all the data that we have about clinical trials and prostate cancer treatment, which are based on conventional imaging?

There's no right answer. Frankly, it will be a long time before we have high-level evidence of how to incorporate molecular imaging into the management of prostate cancer. For me, the take-home message is that we have to use our clinical judgment and make a shared decision with patients about what the molecular imaging shows and how to go about the optimal management for an individual patient.

What could a consensus on some of these treatment recommendations mean for clinical practice in prostate cancer?

Consensus helps to support the notion that a recommendation is more viable. [However], it's important to realize that these are just guidelines. When we come up with a consensus, it's not necessarily based on the highest level of evidence. There could always be some variations in an individual patient that might require you to deviate from a consensus guideline recommendation.

Some of it is related to the patient's disease-specific features that may not be captured in clinical trials. Another really important potential exception to a guideline is patient preferences. We're in an era where we make shared decisions with patients as opposed to a paternalistic, dictatorial recommendation approach. We hear about patients and how intense they want treatment. Do they focus on quality of life? Do they focus on quantity of life? Or something in between?

What other sessions from the Inaugural Prostate Cancer Conference did you want to mention?

We also talked about a very aggressive form of advanced prostate cancer called small cell or neuroendocrine prostate cancer. It comes in many different “flavors” and different shapes. It can be difficult to easily categorize and identify, and we don't really know how to treat it. How important it is, is somewhat debatable. About 15% of patients will develop this aggressive variant of prostate cancer that may require different treatment than we ordinarily use for advanced prostate cancer.

Moving onto the 2023 Genitourinary Cancers Symposium, what data would you like to highlight?

There were some follow-up data on studies involving PARP inhibitors in first-line, metastatic castration-resistant prostate cancer. There was the [phase 3] TALAPRO-2 study [NCT03395197], which tested the role of adding the PARP inhibitor talazoparib [Talzenna] to enzalutamide [Xtandi] vs enzalutamide in first-line, metastatic castration-resistant prostate cancer. The data there were mostly related to radiographic progression-free survival and didn’t have mature OS data.

Then there were follow-up data presented in a study involving a different PARP inhibitor. [The phase 3 study], PROpel [NCT03732820], involved a similar design but a different hormonal agent; abiraterone acetate [Zytiga] with prednisone plus or minus a different PARP inhibitor, olaparib [Lynparza]. There was an overall survival advantage in the biomarker-positive population—of patients who have homologous recombination deficiency.

There was [also] a subgroup in the TALAPRO-2study that did not have the biomarker; they reported some modest improvement in rPFS in that population. The sense is that for the biomarker-negative patients, there is not that much of a benefit, especially since there are no OS data reported. In the biomarker-positive patients, who are expected to have a greater benefit from the addition of a PARP inhibitor, we see much greater extension of rPFS where it's clinically meaningful.

Moving forward, I think there are not going to be that many patients who fit into this category because most patients will have already had a hormonal-signaling agent in metastatic castration-sensitive prostate cancer. Using a second hormonal agent in the metastatic castration-resistant prostate cancer patient was really for the most part, not part of the studies that I just mentioned. I's hard to know how the results from these 2 studies, TALAPRO-2and PROpel, really apply to a modern patient who's first transitioning into metastatic castration-resistant prostate cancer.

References

1. Prostate cancer prognosis. Johns Hopkins Medicine. Accessed February 21, 2023. https://www.hopkinsmedicine.org/health/conditions-and-diseases
2. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115
3. Hussain MHA, Tombal BF, Saad F, et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol. 2023;41(suppl 6):15. doi:10.1200/JCO.2023.41.6_suppl.15