Part 2: SPARTAN Trial Shows Efficacy of Apalutamide for CRPC

Eleni Efstathiou, MD, PhD​

Section Chief of Genitourinary Medical Oncology

Houston Methodist Oncology Partners

Houston, TX

During a live virtual event, Eleni Efstathiou, MD, PhD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the phase 3 SPARTAN trial of apalutamide in patients with castration-resistant prostate cancer.

Targeted Oncology^TM: What is the evidence supporting the use of apalutamide [Erleada]?

[The phase 3 SPARTAN trial (NCT01946204) enrolled] men with nonmetastatic castration-resistant prostate cancer [nmCRPC].^1,2 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 [prostate-specific antigen] 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 metastases 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 97.1 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 [Casodex] 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 metastases 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].³ 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].⁴ 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 adverse events [AEs], fatigue was about 10% higher on the apalutamide arm, which is not too bad.⁴ 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%.⁴ [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.⁵ The rash was resolved for most the 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.⁵ 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.

_REFERENCES

_{1. 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}

_{2. 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}

_{3. 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}

_{4. 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}

_{5. Erleada (apalutamide). Prescribing information. Janssen Pharmaceutical Companies; 2018. Accessed May 7, 2021. https://bit.ly/3hgrNvz}