Practical Considerations for the Treatment of Patients With Metastatic Castration-Sensitive Prostate Cancer

Q: How have the treatment guidelines changed recently for metastatic, castration-sensitive prostate cancer (mCSPC)? How has the use of combination of androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor pathway inhibitor (ARPI) earlier in the treatment paradigm affected patient care and outcomes?

Joseph Renzulli, MD, FACS: If you follow the history of people who presented with mCSPC, they typically didn’t have a lot of [treatment] options early on, and they would just start on hormone therapy. There wasn’t much [of a] role for local therapy for those patients, and their survival was limited. We would see castration resistance develop in people in 24 to 36 months, and [they would have] a very limited overall survival.

With doublet therapy with the introduction of the second-generation, hormonal agents and the CHAARTED [trial (NCT00309985)] data that showed chemotherapy [to be] beneficial in patients with hormone-sensitive, de novo disease, we saw a marked improvement in overall survival in these patients. Not only did their overall survival improve, but their quality of life improved because the disease itself was affecting quality of life.

By treating [the prostate cancer], [the patient experienced] improved quality of life [and] they had less progression of disease in terms of time to progression. The addition [chemotherapy or ARPI treatment to ADT] made a huge impact in both overall survival and patient quality of life. And I think that’s been one of the greatest changes that I’ve seen in my 20 years in urology.

Q: Are most urologists who are treating prostate cancer using these combination approaches in the first-line treatment of patients with mCSPC?

Renzulli: I spent time looking at this when I was [traveling] all over the country presenting to urologists and such, and it was surprising how many clinicians were unaware of the benefits of combination therapy and unaware of the benefits of chemotherapy combined with ADT based on the CHAART­ED data. I think the uptake was slow, unfortunately. Even to this day, there are patients who, unfortunately, do not get standard-of-care therapy, and [they] may just be treated with ADT alone, which is really unfortunate, because [there is a] major difference in survival.

Q: When using ARPI-based doublet therapy, do the results you are seeing in real-world practice reflect what the data showed in terms of improved outcome in the ARCHES (NCT02677896), TITAN (NCT02489318), and LATITUDE (NCT01715285) clinical trials?

Renzulli: In the real-world setting, if [patients receive] the appropriate treatment at the appropriate time, then the outcomes mimic the outcomes in the trial. But, unfor­tunately, as I mentioned, sometimes patients may not get the treatment with the up-front doublet therapy and such, or they might get treated with hormones first, and then [the treating physician will] wait a little longer to use the second therapy or wait until they see progression. So even if [the patient is receiving ARPI-based doublet therapy], they may be getting staggered [treatments].

I don’t know that that is adequate to emulate the out­comes and the trials, but if you use the products the correct way and with the correct temporal approach, I do think that you can achieve those goals, and we have seen that in our practice.

We try to adhere to a multidisciplinary approach so that we can have success, because utilizing the knowledge and the resources of oncology, urology, and radiation oncol­ogy as a combined approach, I think, [gives us superior] outcomes.

Q: Are there any patients who would not be suitable for treatment with an ADT plus ARPI or chemotherapy? What would your treatment approach be for those patients?

Renzulli: With the numerous available oral agents, typi­cally, we’ve been able to find one that would suit all patients or their comorbidities. However, some [patients] aren’t candidates for chemotherapy. But I think that the data has been quite impressive [regarding] oral therapy vs chemo­therapy. In other words, there’s no reason you have to use chemotherapy with ADT. You can use ADT with enzalut­amide, apalutamide, darolutamide, [or] abiraterone. There are plenty of different options. If 1 doesn’t suit a person’s comorbidities, I’m sure one of the others would be able to be utilized with a different [adverse] effect profile that would allow [the patient] to tolerate [the treatment].

It’s very rare that we can only give ADT and nothing else because of a tolerability issue or comorbidity issue. And, in fact, if that patient truly exists, then his life expectancy is probably quite limited to begin with from the other comorbidities that he has, which means prostate cancer will probably not be the cause of his death.

Q: Are you using triplet therapy (ARSI plus ADT plus docetaxel) to treat patients with mCSPC in your practice? Is there a role for triplet therapy?

Renzulli: We started to [use triplet therapy] in our clinic. I do defer triplet therapy to the oncologist. I don’t treat, as a urologist, with the cytotoxic therapies. [Patients] are referred to our [Yale] Cancer Center. And we have our multidisciplinary clinic where we meet together with these patients, but our oncology team has started to use triplet therapy as well. Obviously, we are using it in [patients with the] highest-risk [disease], so they are at risk for failure. But, overall, we’ve seen very positive outcomes in those patients.

Q: Are there any common adverse events observed with the doublet or triplet combination therapies? How do you educate patients about these and how to manage them?

Renzulli: The adverse event that is the most profound is fatigue, and I always say that it’s a cumulative effect. As you add additional therapies, you add fatigue as one of the adverse events for these patients, because you’re really just causing more profound castration. If you [were asked the question], “What’s the number 1 adverse event that stands out?” [the answer certainly would be], “Fatigue.”

In terms of other [adverse events], some of the medica­tions may have a rash associated; [for] others, you have to monitor potassium levels and LFTs [liver function tests], such as with abiraterone. [With] enzalutamide, you want to be thoughtful in patients who may have a history of seizures. They all have their specific risk factors that we either use to avoid that adverse event or to try to limit the toxicity. Sometimes darolutamide, in our approach, has twice-a-day use, but it has a little easier tolerability from an adverse event profile, so we might use that. [We] might stay away from abiraterone and prednisone in [patients with] brittle [diabetes].

It’s become really important to use a personalized ap­proach as opposed to saying, “I’m an abiraterone person, and I only use abiraterone.” I think [treatment] has to be tailored to the individual.

All of our patients at the cancer center meet with a clinical oncology nurse to introduce them to treatment and [to go over] potential things to know. As physicians, we are aggressive about diet to [help patients] avoid the excessive weight gain that can occur. We are aggressive with encouraging exercise—both aerobic [and] resistance exercise—to help maintain muscle mass and bone density. That’s really important. We try to stay aggressive with bone health [by suggesting] supplements and things like that. These [approaches] are how we prepare patients to start on therapy.

Q: How do you talk to patients about the importance of treating mCSPC early and aggressively? Do you find patients are on board with treating the disease aggressively?

Renzulli: In terms of a more layman’s approach to dis­cussion, we try to say, “Look, we want to be aggressive and we want to attack the disease from multiple angles; that’s why we’re using more than 1 therapy. We also want to start earlier, because the lower the burden of disease, theoretically, the more effective these treatments are.”

When [a patient] presents [with prostate cancer, we tell them that although] it’s not a curable situation, necessarily, it’s something that can be controlled and turned into more of a chronic illness and maintained long term.

Most of the gentlemen who present with metastatic disease [want to] be aggressive. I have had a handful of gentlemen who go on treatment and then stop one of the drugs because of a tolerability issue, but that certainly is the exception to the rule, less than 5%.

Q: What challenges might patients face regarding cost and insurance coverage when accessing some of the newer therapies? Are there any strategies to help them deal with those factors?

Renzulli: We try to be helpful with regard to foundation support that exists and help them work through that pro­cess. We have found that sometimes if you try to utilize the oral antagonists, it’s a different pathway than those who get injection therapy. That has been a more dif­ficult process because of the different parts of Medicare that cover injection therapy vs oral therapy. But for the most part, I can’t think of anyone where we couldn’t provide ther­apy because of a cost issue.

Somehow, our team, and certainly I don’t take credit, but the team at the Cancer Center works diligently to try to get everyone medical coverage for drug therapy that they need.

I also know that pharmacists are some­times very helpful. The specialty pharmacy will help [patients] negotiate as well and help them negotiate the opportunity to work with a foundation and such. I find that there’s a lot of support.

Q: Do you have any other advice or message for your colleagues in regard to treating and managing mCSPC?

Renzulli: With the multiple changes that have occurred with screening recommenda­tions in the past, I think it has led to some increase in patients presenting with de novo metastatic disease. So, we as urol­ogists have to be very in tune with the possibility of [patients] presenting with metastatic disease and make sure we’re diligent in how we work these patients up with advanced imaging, especial­ly for high-risk patients.