Alicia K. Morgans, MD, MPH, associate professor of Medicine, Feinberg School of Medicine, Northwestern University, reviewed the clinical trial results for multiple hormonal therapies intended to treat prostate cancer. She explained that many of them show similar outcomes.
During a virtual Targeted Oncology Case-Based Roundtable event, Alicia K. Morgans, MD, MPH, associate professor of Medicine, Feinberg School of Medicine, Northwestern University, reviewed the clinical trial results for multiple hormonal therapies intended to treat prostate cancer. She explained that many of them show similar outcomes.
Targeted OncologyTM: What are the recommended treatments this patient could go on?
MORGANS: [According to] the most recent National Comprehensive Cancer Network [NCCN] guidelines, apalutamide [Erleada], darolutamide [Nubeqa], and enzalutamide [Xtandi] are category 1 recommendations.1 The reason that abiraterone [Zytiga] is in the guidelines, and that I mention it [for possible use], is that the American Urological Association [AUA] lists abiraterone as a category 2 recommendation.
What was the design of the trials that led to the FDA approvals of the novel agents considered for treatment of this patient?
[The trials are] all exceedingly similar, because the same people pretty much collaborated to put together all 3 of these trials. The first is the SPARTAN trial [NCT01946204], which looked at the drug apalutamide. These were all patients who had nonmetastatic CRPC [nmCRPC], and I want to emphasize it [was determined] by conventional imaging [using] CTs and bone scans. They were not using things like Axumin PET or prostatespecific membrane antigen [PSMA] PET.2 Interestingly, in a secondary analysis, when they looked at people who were in the SPARTAN trial, a lot of them had PSMA PETs— 98% of them were positive on a PSMA PET. However, they still would have been included in the trials because they met that nonmetastatic designation by conventional imaging criteria.
Moreover, everybody had a PSA doubling time of less than or equal to 10 months. [SPARTAN] allowed pelvic lymph nodes of less than 2 cm, whereas the others did not. Patients were randomized 2:1 to continue treatment with ADT with or without apalutamide. Every 2 people were treated with apalutamide, 1 with placebo, and everybody continued ADT. The primary end point of the study was metastasis-free survival [MFS]. This was new in the FDA regulatory scheme because normally they based all regulatory approvals of drugs in prostate cancer on overall survival [OS], except mitoxantrone, which was approved on a quality-of-life benefit. This was brand new and really exciting, MFS, which is development of metastatic disease or death from any cause.
What were the characteristics of patients on the SPARTAN trial?
This was a generally older population with a median age of 74, which was replicated in the other 2 trials as well. We also see that a majority of these patients have a really short PSA doubling time. It had to be less than 10 months, but for most people it was less than or equal to 6 months [71.5%].3
What were the efficacy outcomes of the SPARTAN trial?
Those patients who had ADT plus apalutamide had a significantly better MFS than those patients who had ADT alone [40.5 months vs 16.2 months (HR, 0.28; 95% CI, 0.23-0.35, P < .0001), respectively].4 [This is] not unexpected; we know patients with nmCRPC only on ADT are going to progress. It was about 24 months longer when they were treated with the apalutamide in addition to the ADT.
What’s really striking—again, we’ll see this for both of the other drugs—is that no matter what they were treated with for follow-up, these patients in the SPARTAN trial all got apalutamide. When they were on the placebo arm, they were given apalutamide when they progressed. They couldn’t make up for that earlier initiation of apalutamide or, in other cases, enzalutamide or darolutamide, and they ended up having a survival advantage when they were treated earlier with apalutamide.
To me that’s really striking. These patients are treated with many other agents, because they have nmCRPC. They’re [on treatment] for a while, but there was a survival benefit when they got early initiation of the androgen receptor antagonist [APA].
What are some the adverse events (AEs) to keep in mind when looking at this treatment?
The [most common] AEs are things like fatigue and hypertension. Apalutamide also can be associated with some hypothyroidism, so it’s important to monitor thyroid levels, and it can cause a rash in about 10% of patients.5
What were the design and outcome of the PROSPER trial (NCT02003924) that looked at enzalutamide in this patient population?
[It is] almost the same design as the PROSPER trial, but this looked at enzalutamide in nmCRPC by conventional imaging with PSA doubling time of less than or equal to 10 months. Patients were randomized 2:1 to ADT with or without enzalutamide, and the primary end point was still MFS. Secondary end points included OS, quality of life, and all the standard things that we would expect.6
The median age was 73 to 74, so it’s a very homogeneous population. The median PSA doubling time was 3.8 months [(range, 0.4-37.4) for patients on enzalutamide plus ADT, compared with patients on placebo plus ADT at 3.6 months (range, 0.5-71.8)]. The majority of patients had a PSA doubling time of less than 6 months [77% for both arms of the study].
The MFS was 22 months longer when patients were on enzalutamide compared with placebo. [This was a median of 36.6 months compared with 14.7 months (HR, 0.29; 95% CI, 0.24-0.35; P < .0001), respectively.] The treatment delayed the development of metastatic disease or death from any cause by about 2 years [71% reduction of risk] when they got the enzalutamide.
When we look at OS, that early initiation of enzalutamide was something patients could never make up for, as those patients had a longer survival. At the end of their lives, they lived longer because they had that earlier intensification of their therapy, which is really striking and not something I think we all realized might happen. With a median OS of 67 months versus 56.3 months [HR, 0.73; 95% CI, .61-.89, P = .001], the majority of these patients crossed over, got enzalutamide, and then went on to lots of other therapies subsequently.7
What was the safety profile for patients on enzalutamide?
The AEs were what we would expect for enzalutamide. Hypertension [5%] and fatigue [3%] were experienced, and patients also tend to have falls and get some fractures due to strain from the treatment], so we have to be careful. Enzalutamide is a drug that can be associated with a little more gait dysfunction, but it’s relatively rare. Patients with seizures were excluded from PROSPER, the enzalutamide study, as well as from the SPARTAN trial with apalutimide.6
What trial supports the use of darolutamide in this patient?
The ARAMIS trial [NCT02200614] looked at darolutamide [in patients with the same characteristics as the previously discussed trials]. They had a PSA doubling time less than 10 months and had all continued their ADT as they were randomized 2:1 to get darolutamide or placebo.8
Again, 74 is the median age. The majority of these patients [70%] had a PSA doubling time of less than or equal to 6 months, [making them] the highest-risk group. The MFS was 22 months longer for patients treated with darolutamide in addition to ADT, [40.4 months vs 18.4 months respectively (HR, 0.41; 95% CI, 0.34-.050; P < .0001)].
OS was significantly better with darolutamide than with placebo, [as there was a 31% reduction in the risk of death compared with the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = .003)].9 No matter what happens later, they couldn’t make up for [that early initiation].
What were AEs for patients on darolutamide in this trial?
[There was some] fatigue, but it was pretty similar to placebo [15.8% of patients in the darolutamide arm vs. 11.4% in the placebo arm]. There was a greater difference between the other drugs and placebo on the AEs; however, these have not been compared head-to-head. These patients, at least in this study, did not seem to have a higher incidence of falls and patients with seizure in their past and currently could have been enrolled in this trial, which is important to know.8
When comparing these trials together, which agents and outcomes stand out?
They all are prolonging MFS by about 22 to 24 months and they’re all prolonging survival. It’s just up to us to make sure that these patients with nmCRPC gain access to these drugs, because they help them not only prevent metastatic disease but also live longer. What’s not mentioned is that their quality of life was also improved, or at least maintained, throughout these studies.10
Do the differences in the novel hormonal agents translate to clinical consequences?
We sometimes consider drug-drug interactions. Strangely, we’ve run into problems, in the clinic at least. Enzalutamide tends to have a fair number of drug-drug interactions, whereas apalutamide has a number [too]. Darolutamide, maybe because it’s a very different molecule, seems to have fewer [interactions]. This is just something else that people do tend to think about as they’re making these decisions [for treatment].11
The bottom line is that early intervention for patients with nmCRPC has been demonstrated to prolong people with MFS and OS, no matter what we do downstream of this early intervention. Three drugs are approved in the setting—apalutamide, darolutamide, and enzalutamide—and these agents are somewhat distinct in terms of their AEs and safety, and drug-drug interaction profiles.
At the end of the day, though, they all seem to be pretty well tolerated, which is so important in this population that for the most part is relatively asymptomatic, other than the things that we cause with our ADT backbone. We all are very aware of the hot flashes and the fatigue and those kinds of things, but generally, these patients are pretty high functioning. It’s important for us then to keep patients that way as we move forward.
Would you recommend that this patient undergo radiation to the prostate instead of antiandrogen therapy?
It’s odd, in this case this gentleman has refused to do his radiation. We are recommending much less adjuvant radiation because, for example, the RAVES trial [NCT00860652] and RADICALS-RT trial [NCT00541047] both suggested that you can use early salvage radiation when your PSA is about 0.2 and get the same survival benefit as that adjuvant setting. About half of the patients never need to end up getting that radiation because their PSA never gets all the way up to 0.2 in that high-risk population with an undetectable PSA postoperatively.
Ultimately, if the patient has had surgery and has a PSA that has risen to 0.2, we’re getting them in to talk to the radiation oncologist. That’s when we’re thinking about early salvage radiation. Always try to do it before 0.5. In this case, it was odd that this gentleman refused, but that would always be my first step, before using systemic therapy for biochemical recurrence.
1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed March 8, 2021. https://bit.ly/34xiIXZ
2. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
3. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
4. Smith MR, Saad F, Chowdhury s, et al. Apalutamide (APA) and overall survival (OS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): updated results from the phase 3 SPARTAN study. Presented at: European Society for Medical Oncology 2019 Congress; virtual; September 27, 2019. Abstract 8430.
5. Small E. Saad F., Chowdhury S., et al. Final survival results from SPARTAN, a phase III study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
6. Hussain M., Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2018;36(suppl 6):3. doi:10.1200/JCO.2018.36.6_suppl.3
7. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892
8. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671
9. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342
10. Gupta R, Sheng IY, Barata PC, Garcia JA. Non-metastatic castration-resistant prostate cancer: current status and future directions. Expert Rev Anticancer Ther. 2020;20(6):513-522. doi:10.1080/14737140.2020.1772759
11. Morgans AK, Shore N, Cope D, et al. Androgen receptor inhibitor treatments: cardiovascular adverse events and comorbidity considerations in patients with non-metastatic prostate cancer. Urol Oncol. 2021;39(1):52-62. doi:10.1016/j.urolonc.2020.08.003