Rapid Advances Underscore Significance of Patient Selection in Metastatic Prostate Cancer

Atish D. Choudhury, MD, PhD

Mature data from several phase III trials, aside from confirming a survival benefit with docetaxel, androgen receptor (AR)-targeted therapy, and radiation therapy in patients with metastatic prostate cancer, underscore the importance of stratifying patients by volume of disease, said Atish D. Choudhury, MD, PhD.

“Certainly, we have a paradigm in which we generally start with an aggressive antiandrogen, after which our standards split off. Certainly, some patients are candidates for chemotherapy after that. It’s an opportunity for genetic characterization and understanding the different genetic vulnerabilities between patients,” said Choudhury.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Choudhury, co-director of the Prostate Cancer Center, senior physician and instructor in medicine, Harvard Medical School, Dana-Farber Cancer Institute, detailed the advances in metastatic prostate cancer in light of updated analyses from several clinical trials and forthcoming research in the field.

OncLive: What are some of the key advances in metastatic prostate cancer?

Choudhury: I had prepared a slide deck on metastatic prostate cancer in 2018, and I had to redo it completely with all the data we received over the past year. I would categorize the advances that have been made over the past year in 2 separate categories: the treatments that show a benefit in progression-free survival (PFS) and overall survival (OS) and the identification of patients who benefit from these particular treatments. In terms of treatment advances, I spoke about chemotherapy, AR-targeted therapy, and radiation therapy and how they play a role in metastatic prostate cancer.

In early 2018, an updated analysis of the CHAARTED study was published in the Journal of Clinical Oncology. In the trial, patients were randomized to receive androgen deprivation therapy (ADT) with docetaxel compared with ADT alone. Results showed an OS benefit with early docetaxel. With longer follow-up, we're able to categorize patients by volume of disease. Patients classified as having high-volume disease have visceral disease greater than or equal to 4 bone metastases, at least 1 of which has to be outside of the vertebrae or the pelvis.

We see that the survival benefit with docetaxel seems to be concentrated in patients with high-volume disease compared with low-volume disease. The hazard ratio (HR) for survival for patients with low-volume disease was approximately 1, so there’s really no benefit there. That doesn't mean that patients with low-volume disease don't respond to docetaxel, it just means that they don't seem to have a survival benefit from receiving it when they're first diagnosed. These patients have a good enough response to ADT that, if they receive docetaxel at the time of castration resistance, there doesn't to be any adverse impact on OS. These findings are very similar to what was seen in the GETUG-AFU 15 trial, which after stratifying patients by volume of disease, showed an HR of 1 in those with low-volume disease [for OS].

Regarding AR-targeted therapy, the updated analyses of the LATITUDE study show that the OS benefit held up with longer follow-up. The OS benefit with abiraterone acetate (Zytiga) seems to benefit patients with both high- and low-volume disease. The most critical piece of information that we've received from the updated analysis is the PFS2 endpoint, which is the time to progression from the second treatment after a diagnosis of metastatic disease. PFS2 was significantly prolonged in patients who received ADT and abiraterone compared with patients who received ADT alone. We're not influencing the response to next therapy by giving abiraterone upfront; that’s very reassuring to know that there doesn't seem to be any harm associated with frontline abiraterone.

I also presented the analysis of the ARCHES study with enzalutamide (Xtandi). This study demonstrated a radiographic PFS advantage with frontline enzalutamide compared with ADT alone. The OS data from that analysis are not yet mature, so we don't know if that is improved. In the TITAN study, patients were randomized to ADT and apalutamide (Erleada) compared with ADT alone. That trial was interrupted early based on review that suggested that both primary endpoints of radiographic PFS and OS seemed to improve with apalutamide. Patients who were randomized to placebo were then offered apalutamide as part of the study. Those data have not yet been presented, so we're very eagerly awaiting those results.

The third major advance is the role of radiation to the prostate. Many retrospective studies have suggested that patients who get radiation seem to live longer than those who did not. However, retrospective studies are limited because of selection bias.

Two randomized studies were presented over the last year: the HORRAD and STAMPEDE studies. In both of those studies, there didn't seem to be a survival benefit in the total patient population who received radiation. However, patients who had less than 5 bone metastases in the HORRAD study had an HR of 0.68, so there was a trend towards favorable OS in patients with fewer bone metastases. That value did not reach statistical significance because it was a relatively small study.

In the STAMPEDE trial, which was a much larger study of at least 800 patients with low-volume disease, those who received radiation to the prostate experienced a statistically significant benefit in terms of OS. The HR was about the same, at 0.68, suggesting that these are believable and reproducible results. Now, we do consider radiation to the prostate in patients with low-volume metastatic disease.

Regarding all of these studies, it turns out that volume status whether high-volume or low-volume has a huge impact on what patients benefit from. Patients who have high-volume disease have a much higher likelihood of benefitting from chemotherapy, whereas patients with low-volume disease seem to be more likely to have a survival benefit with radiation to the prostate. Moreover, the survival benefit with abiraterone seems to be across patients with low- and high-volume disease. There are a lot of questions about how anatomic distribution of metastases reflects the underlying biology. We don't really know that relationship yet.

What are some emerging treatment modalities?

There are many different treatment approaches for patients with metastatic prostate cancer that are showing a great deal of promise. When I discuss new treatment options with patients, I put them into buckets—–one is chemotherapy, one is targeted therapy, one is immunotherapy, and one is radiopharmaceuticals, which is a targeted way to deliver radiation to particular sites of disease. For chemotherapy, we're learning that carboplatin is a very effective drug for a subset of patients with metastatic prostate cancer. There are 2 different patient populations that it seems to benefit. One is patients with DNA damage repair, so these are the patients with BRCA1/2 and ATM mutations. Then, researchers at The University of MD Anderson Cancer Center has defined a molecularly aggressive variant population by losses of 2 of the 3 following tumor suppressors: PTEN, TP53, and RB1. In both the case of DNA damage-repair alterations and aggressive variant features, carboplatin seems to be of benefit.

As far as targeted therapies are concerned, the most prominent therapies are those that target the AR. We’ve learned that there are some promising approaches that target signaling pathways other than the AR pathway; these are under investigation. For example, patients who have lost PTEN seem to be more responsive to downstream inhibition of AKT. AKT inhibitors are one of our most interesting kind of targeted agents that we're pursuing.

Then, there are PARP inhibitors, which seem to benefit patients with BRCA1/2 mutations. It’s interesting to see where ATM plays a role in terms of the DNA damage response. The original publication demonstrating a benefit with olaparib (Lynparza) in the metastatic setting seemed to include patients with ATM loss. However, in the TRITON study, patients with ATM mutations did not seem to have a response to PARP inhibitors. Now, we seem to think that PARP inhibitors [are only of benefit] to patients with BRCA1/2 alterations. We don't where ATM is going to fall in terms of this realm.

Everything else in the targeted realm is fairly early on in the process, so we'll have to see where things go over time. As far as immunotherapy is concerned, we know that 10% of unselected patients with metastatic castration-resistant prostate cancer seem to have a prostate-specific antigen (PSA) response to pembrolizumab (Keytruda), based on the KEYNOTE-199 trial. We're very interested to see who those 10% of patients are, and if there's a way to combine pembrolizumab with another agent to potentially increase that response rate.

Those kinds of combination studies are ongoing. Certainly, we're interested to see what the combination of pembrolizumab plus enzalutamide ends up looking like, as well as what the combination of pembrolizumab with PARP inhibitors ends up looking like. Moreover, [it will be interesting to see] whether there is a benefit to combining pembrolizumab with other checkpoint inhibitors and if that shows increased activity compared with pembrolizumab alone.

At the 2019 Genitourinary Cancers Symposium, we learned that there is a favorable response rate to the combination of ipilimumab (Yervoy) and nivolumab (Opdivo). However, the discontinuation rate was prematurely seen in over 50% of patients. We're just not sure whether the toxicity profile of that particular combination benefits those patients. Though, there was an added signal in patients with high tumor mutational burden (TMB) compared with what’s been seen in patients with low TMB. We're very interested to see if this is a biomarker that holds up and if this is a treatment option for that subset of patients.

The last category is radiopharmaceuticals. We know the role of radium-223 dichloride (Xofigo) in terms of improving OS and decreasing the rate of skeletal-related events in patients with metastatic prostate cancer. We're learning that these radiopharmaceuticals that target prostate-specific membrane antigen and are conjugated to a radioactive isotype of lutetium seem to have pretty pronounced activity in decreasing PSA levels and leading to radiographic responses in a subset of patients. Now, we're very interested to see how these agents hold up in phase III trials.

Where does this leave sequencing strategies?

We're trying to learn how to sequence these agents, how to combine them, and how to select particular patients for them. It's clear that all of these treatments have adverse events. Quality of life is a very critical component in prostate cancer, where patients can live for years even after a metastatic diagnosis. We have to consider when it is appropriate to introduce the toxicity of a particular agent for its benefit.

We know that patients who have particular DNA mismatch repair seem to benefit from checkpoint inhibitors. We know that patients with defects in BRCA1/2 pathways seem to benefit from PARP inhibitors. Now, we're investigating which patients might respond to other targeted therapies, as well as those who might respond to radiopharmaceuticals so that we can introduce these agents at the right time for the right patient.