New Treatment Indications Boost Survival in Metastatic Hormone-Sensitive Prostate Cancer

William Oh, MD

Androgen receptor (AR) inhibitors have become staples of treatment alongside docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC), according to William K. Oh, MD, citing several clinical trials as showcasing benefit with this class of agents in this setting.

Previously, docetaxel chemotherapy showed an overall survival (OS) benefit versus standard-of-care therapy as frontline therapy in patients with mHSPC in the phase III CHAARTED¹ and STAMPEDE² trials.

Subsequently, the AR inhibitor abiraterone acetate (Zytiga) demonstrated an OS advantage with androgen deprivation therapy (ADT) and prednisone versus ADT alone in treatment-naïve patients in the phase III LATITUDE trial. Data from the trial, which showed a 38% reduction in the risk of death with the addition of abiraterone and prednisone to ADT, served as the basis for the regimen’s approval in February 2018 for this indication.³

More recently, efficacy data from the TITAN trial showed that the addition of the AR inhibitor apalutamide (Erleada) to ADT led to a 2-year OS rate of 82.4% versus 73.5% with ADT alone (HR, 0.67; 95% CI, 0.51-0.89; P = .005) in this patient population. In September 2019, the FDA approved the regimen for use in this setting.⁴

Moreover, the ENZAMET trial showed a 3-year OS rate of 80% in patients with mHSPC who received the AR inhibitor enzalutamide (Xtandi) and standard therapy versus 72% in those who received a different nonsteroidal antiandrogen (HR, 0.67; 95% CI, 0.52-0.86; P = .002).⁵ Data from ENZAMET echoed those reported from the phase III ARCHES trial, which served as the basis for the December 2019 FDA approval of enzalutamide in this setting.⁶

“In addition to data from the CHAARTED, STAMPEDE, and LATITUDE trials, which [collectively] showed that 6 cycles of docetaxel and ongoing treatment with abiraterone and prednisone results in a significant improvement in survival, we now have data showing that enzalutamide and apalutamide improve survival as well,” said Oh, chief of the Division of Hematology and Medical Oncology of Mount Sinai Health System and deputy director of Tisch Cancer Institute.

As such, treatment can be tailored to patients according to their age, comorbidities, and personal preferences, added Oh. As these agents move into earlier lines of treatment, the field will have to learn how to exploit new mechanisms of action to overcome acquired resistance.

In an interview with OncLive, Oh, who is also a professor of medicine and urology and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics at Mount Sinai Hospital, shed light on how he approaches treatment in patients with mHSPC.

OncLive: Could you shed light on the ENZAMET trial and the implications of these findings?

Oh: ENZAMET was a large clinical trial that randomized patients with newly diagnosed mHSPC to receive ADT plus enzalutamide at a standard dose or a standard antiandrogen, such as bicalutamide or flutamide. The results showed a significant survival benefit in favor of enzalutamide. This finding wasn't particularly surprising, because we saw a very similar effect in LATITUDE and STAMPEDE with abiraterone, which isn’t dissimilar to enzalutamide. About 45% of patients [on the trial] were allowed to receive physician’s choice of chemotherapy. In other words, it wasn’t a prespecified randomization.

One of the biggest questions regarding CHAARTED and LATITUDE was whether chemotherapy is better than AR-targeted therapy in mHSPC. ENZAMET provided some intriguing, albeit not definitive, information in this regard. All of the benefit with enzalutamide seemed to be in patients who did not receive chemotherapy. There may have been some cross reactivity between 6 cycles of docetaxel and the benefit of enzalutamide; however, the data aren’t conclusive. At this point, we can't say whether chemotherapy is better than AR-targeted therapy or whether there is synergy between the agents. However, there appears to be continued evidence that one agent or the other is the preferred approach. Combining these therapies is not standard of care.

Now that there are 4 drugs, could you discuss patient selection?

The biggest challenge is that we can’t do cross-trial comparisons. You can't tell if chemotherapy or an AR-targeted therapy is more valuable, so clinicians are left to their own devices. We have to consider the patient’s age, comorbidities, and their personal preferences.

For example, many patients are averse to chemotherapy. However, patients can complete chemotherapy within 4.5 months or so. Conversely, with abiraterone, enzalutamide, or apalutamide, patients have to stay on the combination of ADT plus that AR-targeted therapy continuously.

Another consideration is cost. Some patients’ copays for an oral or intravenous therapy may be prohibitive. Docetaxel has become the cheapest available option, and since it's an equivalent option, that may be the deciding factor for some patients.

Toxicity differences exist between the AR-targeted therapies, apalutamide, enzalutamide, and abiraterone. For example, abiraterone requires prednisone. If the patient is a brittle diabetic, they shouldn't go on prednisone, even if it's a low dose. Abiraterone is also more so associated with liver function abnormalities and more significant cardiovascular health issues. Cross-study comparisons make it difficult [to know for sure], but I do believe that AR-targeted therapies have an increased risk of exacerbating an underlying cardiovascular issue. With apalutamide, patients may have a higher risk for rash. With enzalutamide, there’s a risk for muscle weakness and fatigue. Each agent has tolerable adverse events.

Are other notable emerging therapies under investigation in this space?

The treatments that were tested in mHSPC were also evaluated in castration-resistant prostate cancer (CRPC). [The agents are] moving into earlier lines of treatment because those patients are the ones who are at the greatest risk of dying from cancer. We know olaparib (Lynparza) has a significant benefit in patients with metastatic CRPC who have already received first-line AR-targeted therapy. If a patient has a germline BRCA mutation and they present with metastatic disease, should those patients receive a drug like olaparib upfront? We don’t know yet, but that is where [research is] headed.

We're increasingly going to see patients selected for treatment according to their molecular profile. For example, patients with microsatellite instability—high (MSI-H) tumors are eligible for pembrolizumab (Keytruda). Should those patients receive standard ADT and chemotherapy or standard ADT and abiraterone? Or, should they get pembrolizumab in that setting? If I had a patient with an MSI-H tumor, I would strongly consider giving them a checkpoint inhibitor like pembrolizumab because responses can be very dramatic. Despite all the benefits we have seen with drugs, such as docetaxel, abiraterone, enzalutamide, and apalutamide, the overall effect is still modest. These patients are still progressing and dying of their cancer. PARP inhibitors and checkpoint inhibitors may have more of a benefit if you use them earlier [in the treatment journey]. However, we need to do more trials to prove that [this is the case].

What are the greatest challenges that still remain in mHSPC?

Two [challenges come to mind]. If we start moving all our treatments upfront and patients relapse on them, [then we will have] run out of options. This is happening in bladder cancer, and it has happened already in renal cancer. It’s great that patients experience a longer benefit when we move these agents earlier, but the cancer will [eventually] become resistant [to the agents] and proliferate. I have patients who have exhausted all standard options because we have moved these agents earlier [in treatment].

The other challenge is finding new mechanisms and developing treatments that exploit resistance mechanisms. We don't understand a lot about resistance, even AR resistance. We've learned about neuroendocrine prostate cancer as a pathway of resistance, but we don't fully understand how it happens. [We know that there] are different forms of treatment-related resistance. Some patients have a relatively low prostate-specific antigen (PSA) [level], but are they all small cells? Some patients have 0 PSA, which may be a pure small cell, but that's pretty rare. We don't really understand why these patients are progressing. Until we fully understand the biology of what's happening, it's very hard for us to treat these patients effectively. Also, as we understand more about the biology of resistance, we’ll be able to develop more targeted treatments.

What are some important takeaways for community oncologists who may not be seeing as many cases of prostate cancer as those in the academic setting?

Metastatic disease is still treated by medical oncologists and urologists. Historically, urologists considered themselves to be the gatekeepers of prostate cancer because they generally made the diagnosis. They did the biopsy. Traditionally, they have given drugs like LHRH agonists, which are easy to give in a urology office. I do believe that the medical oncologist is a really critical component of [the patient’s care]. We’re not doing surgical procedures, but we're giving medical therapies to patients. I’ve worked with many great urologists over the years who want to do multidisciplinary care.

However, I believe some community urologists don't refer patients soon enough [to specialized centers]. If a patient is a candidate for enzalutamide, abiraterone, or radium-223 dichloride (Xofigo), they can refer the patient directly to nuclear medicine. I recognize that part of the [rationale] is that they can care for the patient themselves, and that may be true. However, I would encourage community oncologist to build bridges to urology, and refer them as early as possible—especially in the case of metastatic disease.

We know more about molecular testing, systemic therapy, and earlier incorporation of chemotherapy. The one treatment [urologists] don't give is chemotherapy, and many patients never receive it as a result. Multiple trials, including the CHAARTED and CARD trials, have shown the benefit of chemotherapy. In the CARD trial, third-line cabazitaxel (Jevtana) had a survival advantage compared with a second AR-targeted therapy. If our goal is to keep patients alive with the best quality of life for as long as possible, it's incumbent on the oncologist to build bridges to the urologist.

What is the role of radiopharmaceuticals in this space?

Radium-223 dichloride was approved several years ago based on a survival benefit; however, it has modest OS benefit. The [radiopharmaceutical] has some palliative benefit in terms of bone improvement and bone pain. Investigators have been looking to improve upon radium-223 dichloride with targeted therapy.

One area that's been under active investigation is lutetium-177 prostate-specific membrane antigen (PSMA; Lu-PSMA). PSMA is widely expressed in mCRPC, especially after prior therapies; it represents a relatively tumor-specific target. Lutetium-177 is a radiopharmaceutical that is tied to a small molecule. Lu-PSMA-617 is the most encouraging small molecule, although other antibodies and other targets for PSMA exist. Lu-PSMA-617 is a promising way of delivering a radioactive payload to PSMA-producing cancer cells. Some of the phase II studies [with the therapy], particularly those that have come out of Australia and Germany, have shown very high response rates of 75% in patients with PSMA-positive disease. We’ll have to wait and see if this [therapy] is associated with a survival benefit, but it appears to be associated with very durable and significant clinical responses. It’s very promising as a potential new treatment approach in mCRPC.

References

1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi: 10.1056/NEJMoa1503747.
2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi: 10.1016/S0140-6736(15)01037-5.
3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174.
4. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307.
5. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi: 10.1056/NEJMoa1903835.
6. Xtandi (Enzalutamide) approved by U.S. FDA for the treatment of metastatic castration-sensitive prostate cancer [news release]. Pfizer. Published December 16, 2019. https://bit.ly/2tpujIV. Accessed February 7, 2020.