Three Similar Trials Lead to Adverse Event Comparisons for Use in nmCRPC

Case-Based Peer Perspectives Spotlight Live, Case-Based Roundtable Meeting Spotlight September 2021: Solid Tumors,
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Based on 3 clinical trials, suggest that when managing toxicities in patients with non-metastatic castration-resistant prostate cancer, oncologists should look at the delta instead of the absolute numbers.

Eleni Efstathiou, MD, PhD, an oncologist in Genitourinary Medical Oncology ay The University of Texas MD Anderson Cancer Center in Houston, TX, discussed the case of a 57-year-old Black man with non-metastatic castration-resistant prostate cancer (nmCRPC), during a Targeted Oncology Case-Base Roundtable event.

Targeted OncologyTM: What is the recommended approach for a patient with nonmetastatic castration-resistant prostate cancer (nmCRPC)?

EFSTATHIOU: It is important to follow the NCCN [National Comprehensive Cancer Network] guidelines to get [insurance] reimbursement for our patients.1

The NCCN guidelines maintain that conventional imaging [should be used to determine whether there are metastases present, making] the definition of nmCRPC an administrative one. If we could get very detailed imaging, we would probably find [metastases]. A trial from Germany found that 75% of patients had visible metastases on a PSMA [prostate-specific membrane antigen] PET scan.2

Testosterone levels should be assessed to confirm castration.1 If the PSA doubling time is over 10 months, the preference is observation. Alternatively, especially if the patient is extremely anxious, a secondary hormone therapy, such as bicalutamide [Casodex], can be added. In fact, there’s a very old practice where they would use a very low dose of dexamethasone or prednisone [for these cases]. When the PSA doubling time is less than 10 months, the preferred regimens, based on category 1 level evidence, are apalutamide [Erleada], darolutamide [Nubeqa], and enzalutamide [Xtandi].1 Other recommended regimens are secondary hormone therapies.

For a PSA doubling time of more than 10 months, when would you use secondary hormone therapy?

In those cases, the concern is reimbursement [as the labels for the drugs mentioned above say that they are indicated for] rapidly increasing [PSA levels]. However, the labels don’t list the PSA doubling time, so this might result in a back-and-forth with the insurance company. My concern is that the moment you start these agents, the clock starts counting for a lengthy exposure to enhanced androgen signaling inhibition, which might lead to more osteoporosis and cardiovascular AEs [adverse events]. I try to explain this to my patients to convince them to delay starting treatment.

When would you decide to image?

If the PSA doubling time is less than 10 months, I image regardless of the PSA level. If the doubling time is more than 10 months but the PSA level is above 2, I image as well. This gives me a baseline. Then we can discuss with the patient whether we are going to look at things every year or not. [I do this because there are rare cases] where there is progression of disease without the PSA going up. These are the highly aggressive prostate cancers, so it is important to monitor them. These patients, who might have DDR [DNA damage repair] mutations, such as a BRCA2 mutation, might fall under that category.

What is the evidence supporting the use of second-generation nonsteroidal antiandrogens for CRPC?

[Three trials analyzed the efficacy and safety of these drugs for CRPC:] SPARTAN [NCT01946204], PROSPER [NCT02003924], and ARAMIS [NCT02200614]. These trials are all very similar, allowing for high reproducibility, which is necessary for changing clinical practice.…For full disclosure, I am an investigator for the PROPSER trial, which is the one that assessed enzalutamide.

What is the evidence supporting the use of apalutamide?

[The phase 3 SPARTAN trial enrolled] men with nmCRPC.3,4 The trial allowed patients with localized disease such as pelvic nodes, less than 2 cm and not bulky, below the iliac bifurcation or evidence of residual disease, and the PSA doubling time had to be less than 10 months. The randomization was 2:1, apalutamide vs placebo, with patients having a 70% chance of getting the drug.

The primary end point was MFS [metastasis-free survival], which included time to detection of metastasis by imaging or death. Upon progression, patients who were on the placebo arm were offered abiraterone [Zytiga], which was good because this was not available in all countries at the time. Then they evaluated the time until the second progression, which is important to know in order to decide whether to give the drug earlier or later.

The median age of participants was 74 years old, with a range from 48 to 97.3 The PSA doubling time was about 4.5 months for both arms, which were very well balanced. An important aspect to point out is that despite the fact that most of these patients had previous continuous exposure to androgen deprivation, only 10% were getting prophylaxis for osteopenia or osteoporosis. We know that’s not acceptable. Another interesting point is the classification of local disease. Approximately 15% of the men on the trial had local regional disease, and just over 20% had not received local regional therapy. This is quite interesting and points to the fact that there are still patients who are not offered primary treatment at the appropriate time. Finally, 70% of patients received prior treatment with first-generation [antiandrogen agents] such as bicalutamide or flutamide [Eulexin]. But it is not clear whether they got it for a flare or as a treatment.

The results from these trials are outstanding. The primary end point was met, and the difference in time to metastasis or death was 2 years between apalutamide and placebo [median MFS, 40.5 vs 16.2 months; HR, 0.28; 95% CI, 0.23-0.35; P < .0001].5 There was also a big median OS [overall survival] benefit [73.9 vs 59.9 months; HR, 0.78; 95% CI, 0.64-0.96; P = .0161].6 After the MFS results came out, there was some debate about whether there was a real benefit to the patients, but the OS benefit results showed that there was a clear benefit. The question that remains is how to ensure that you don’t lose patients from other causes that are associated with prolonged androgen deprivation.

Looking at the most frequent AEs, fatigue was about 10% higher on the apalutamide arm, which is not too bad.6 The other frequent AEs were hypertension and diarrhea, both about 8% higher. I think the diarrhea might have been due to the formulation of the capsule rather than the drug itself. The biggest difference was in the number of falls, which subsequently led to fractures as well. The explanation for this is not clear. It could be due to a [blood-]brain barrier event. Another possible explanation is that it is due to the loss of muscle tone because of the exposure to enhanced androgen signaling inhibition. There was also a higher rate of arthralgia in the apalutamide arm. In my experience, you have to protect these patients by providing bone-sparing agents and monitoring with DEXA [dual-energy x-ray absorptiometry] scans every couple of years.

I want to bring to your attention the decrease in weight in the apalutamide arm, which was 20% vs 6%.6 [This] was probably associated with loss of muscle.

Another important factor to consider is that 24% of patients on the apalutamide arm experienced a skin rash, 5.2% of which was a grade 3 rash.7 The rash was resolved for most patients [81%]. In my practice, I’ve only had to stop apalutamide with 1 patient, who had allergies to almost all antibiotics. Very few patients needed systemic corticosteroids.7 In most cases, the rash was manageable using a topical ointment or antihistamine. However, there was recurrence of the rash in approximately 50% of patients who were rechallenged with apalutamide. [The rash led to dose interruption in 28%, dose reduction in 12%, and discontinuation in 9% of cases.] I’ve had to reduce the dose in a few patients, and, in my experience, this is more prominent in the Asian population.

What is the evidence supporting the use of enzalutamide?

The evidence for the use of enzalutamide comes from the phase 3 PROSPER trial.8 As I said above, the study design is very similar. Patients with nmCRPC, PSA doubling time less than 10 months, and baseline PSA over 2 ng/mL were randomized 2:1 to placebo. The end points were also identical; the primary end point was MFS [and the main] secondary end point was OS. Other secondary end points were [safety, time to PSA progression, time to use of new antineoplastic therapy, PSA response, and] QOL [quality of life].

The median age was 74 years, the PSA doubling time was just below 4 months, and only 10% were on bone-targeting agents at the beginning of the study.

[The median MFS was about 22 months longer with enzalutamide compared with placebo, corresponding to a 71% reduction in the relative risk of radiographic progression or death.8,9] There was almost a 2-year difference in OS [HR, 0.73; 95% CI, 0.61-0.89; P = .001], which is phenomenal.

I’ve had many discussions regarding how we report AEs. Ideally, certain aspects should be evident from the data set. For example, with fatigue, most data sets focus on reports over grade 3. But a patient with grade 3 fatigue is in bed all day, so it’s important to know the rate of grade 2 fatigue, which is also significant. That was not very clearly reported, nor was the rate of falls.

There weren’t any reports of a rash with enzalutamide.8 An important thing to point out with this study is the number of deaths due to AEs on trial for any reason. There were 32 cases [3%] in the enzalutamide arm and 3 cases [1%] in the placebo arm. The difference between the 2 is only 2%, but it is a big deal because we’re talking about deaths. In fact, there was a big discussion during the initial presentation of the data set, because there were many patients who died after discontinuing enzalutamide that were not accounted for. It seems that these are mainly cardiovascular events. I’m not pointing the finger at enzalutamide; rather, I believe that there is a need to closely monitor patients who are on prolonged androgen deprivation.

What is the evidence supporting the use of darolutamide?

Darolutamide was the last of these agents to be studied, and data from the phase 1 and 2 trials indicated that it had a good target effect, without the AEs. The phase 3 ARAMIS trial confirmed this.

This phase 3 trial had a similar design to the other 2: men with nmCRPC with a baseline PSA over 2 ng/mL, a PSA doubling time of less than 20 months, and an ECOG performance status of 0 or 1, with the same randomization and primary and secondary end points.10 A difference between darolutamide and apalutamide and enzalutamide is that the pills must be taken twice a day, instead of once a day, because of the half-life of the drug. On the bright side, the pills are pretty small.

This trial was done mainly in Europe, but the patient characteristics were similar to the other 2. The median age was 74 years, and the median time from diagnosis was 86 months.10 Between 17% [darolutamide] and 29% [placebo] of patients had regional disease. The median PSA doubling time was 4.4 months. Even though the study design allowed for up to 20 months, this median was very close to the one in the SPARTAN trial, which was 4.7 months. Most patients [76%] had received 2 or more previous hormonal therapy agents, probably bicalutamide and flutamide.

With this study, there were again almost 2 years [22 months] of difference in MFS [HR, 0.41; 95% CI, 0.34- 0.50; P < .0001].10 The median follow-up time for this study is much shorter, 17.9 months for MFS and 29 months for OS.10,11 Despite this shorter follow-up period, the HR for OS is positive [HR, 0.69; 95% CI, 0.53-0.88; P = .03].11 With this, we have 3 trials that meet all the criteria of read-out, MFS, OS, and all the secondary end points. All the weight is now shifted to the safety.

When it comes to all-grade AEs, there is not yet much of a difference between the 2 arms except for fatigue.10 This is really impressive, but we have to monitor further. These results left me thinking about whether I was going to see the same with my patients, and I have.

How would you compare the results from these trials?

If we look at the results from these 3 trials at once, we see that they have very comparable and positive outcomes for MFS and OS.12 The patients in the placebo arms were subsequently offered crossover or, in the SPARTAN trial, they were given abiraterone.

These are big trials, with almost 5000 patients combined.3,9,11 Looking at the delta, the difference between drug and placebo, in the AEs of interest, though you can’t compare directly, enzalutamide has a slightly stronger signal when it comes to fatigue. The rash only showed up with apalutamide. Both apalutamide and enzalutamide show an increase in the number of falls, which is in line with the central nervous system effect. Of course, an increase in falls is related to an increase in fractures as well. Although mental impairment disorders are not easy to capture, we see a little bit more with enzalutamide, as expected.

I want to bring up a very important point. The apalutamide trial is the only trial that was recording the AEs on a month-to-month basis, for at least the first 12 months. PROSPER and ARAMIS were recording every 4 months. That makes a big difference in the percentages reported. That’s why we should be looking at the delta and not the absolute numbers.


1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed March 30, 2021.

2. Hoffmann MA, Buchholz HG, Wieler HJ, et al. PSA and PSA kinetics thresholds for the presence of 68Ga-PSMA-11 PET/CT-detectable lesions in patients with biochemical recurrent prostate cancer. Cancers (Basel). 2020;12(2):398. doi:10.3390/ cancers12020398

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. Small EJ, Saad F, Chowdhury S, et al. Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7):144. doi:10.1200/JCO.2019.37.7_suppl.144

5. Smith MR, Saad F, Chowdhury S, et al. 2522 - Apalutamide (APA) and overall survival (OS) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): updated results from the phase 3 SPARTAN study. Ann Oncol. 2019;30(suppl 5):v325- v355. doi:10.1093/annonc/mdz248

6. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516

7. Erleada (apalutamide). Prescribing information. Janssen Pharmaceutical Companies; 2018. Accessed May 7, 2021.

8. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6):3. doi:10.1200/JCO.2018.36.6_suppl.3

9. 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

10. 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

11. 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

12. 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