Second-generation antiandrogen in an elderly patient with high-volume mCSPC

Presentation and management
An 80-year-old male presented with rectal bleeding and elevated prostate-specific antigen (PSA; 100 ng/mL) in October 2021. Biopsy of rectal tissue showed adenocarcinoma of the prostate. Molecular testing found that the disease was microsatellite instability (MSI)–stable, with no targetable mutations; tumour mutational burden was zero. His Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 1.

Dual tracer prostate-specific membrane antigen (PSMA) and fludeoxyglucose (FDG) PET-CT scan revealed multiple lymph nodes with metastases to the peritoneum and lung. The disease was subsequently classified as high-volume, de novo metastatic castration-sensitive prostate cancer (mCSPC) that eroded through the rectal wall. Bilateral orchiectomy was performed and apalutamide was started in the same month.

The patient’s PSA level dropped to 70 ng/mL after receiving apalutamide for 1 month, dropping to 48 ng/mL after 2 months of treatment. Apalutamide was well tolerated, with mild skin dryness and itchiness as the only adverse events (AEs), which did not affect sleep and were well controlled with an oral antihistamine and topical application of liquid paraffin moisturizers. The patient’s renal and liver functions remained normal.

In October 2022, repeat dual tracer PET-CT scan showed >50 percent shrinkage in the rectal mass and iliac lymph nodes. (Figure) Last seen in September 2023, the patient continued to show good radiological, biochemical and clinical response to apalutamide, after almost 2 years of treatment. His latest PSA level was 34 ng/mL (August 2023).

The patient remains active and asymptomatic, with no rectal bleeding and enjoys good quality of life (ECOG PS, 1). The plan is to continue treatment with apalutamide until disease progression or intolerance, along with regular monitoring every 6–8 weeks.

Discussion
In mCSPC, disease volume is a deciding factor in the choice of therapy because de novo, high-volume mCSPC is associated with the worst prognosis (5-year overall survival [OS], 20–30 percent).¹ In patients with high-volume mCSPC, the addition of an androgen receptor inhibitor (ARI), such as apalutamide, or docetaxel to androgen deprivation therapy (ADT) has improved outcomes and become the standard of care.¹ Doublet therapy improves prognosis of mCSPC by delaying castration resistance vs ADT alone.²

Apalutamide is an oral ARI approved for treatment of mCSPC patients who have had bilateral orchiectomy or are receiving concurrent drug-based ADT.³ Its long-term safety and efficacy were demonstrated in the randomized, placebo-controlled, phase III TITAN trial.

In TITAN, 1,052 patients with mCSPC (high-volume disease, 63 percent) received ADT with either apalutamide or placebo.⁴ At the first interim analysis, apalutamide significantly improved OS (hazard ratio [HR], 0.67; 95 percent confidence interval [CI], 0.51–0.89; p=0.005) and radiographic progression-free survival (PFS; HR, 0.48; 95 percent CI, 0.39–0.60; p<0.001) vs placebo. Because OS and all secondary endpoints consistently favoured apalutamide over placebo across patient subgroups, treatment was unblinded to allow placebo recipients to cross over into the apalutamide arm.^4,5

At the final analysis, with a median follow-up of 44 months, apalutamide significantly reduced the risk of death vs placebo by 35 percent in the overall population (median OS, not reached [NR] vs 52.2 months; HR, 0.65; 95 percent CI, 0.53–0.79; p<0.0001), 30 percent in patients with high-volume disease (median OS, NR vs 38.7 months; HR, 0.70; 95 percent CI, 0.56–0.88; p=0.002), and 47 percent in those with low-volume disease (median OS, NR for both; HR, 0.53; 95 percent CI, 0.35–0.79; p=0.002).^5,6 Even after adjustment for crossover, the risk of death was significantly reduced by 48 percent in the overall population (HR, 0.52; 95 percent CI, 0.42–0.64; p<0.0001), and by 39 percent (HR, 0.61; 95 percent CI, 0.49–0.78; p<0.0001) and 66 percent (HR, 0.34; 95 percent CI, 0.22–0.53; p<0.0001) in patients with high- and low-volume disease, respectively.^5,6 Apalutamide also prolonged PFS and significantly reduced the risk of second progression or death by 38 percent vs placebo in the overall population.⁵

Furthermore, apalutamide significantly delayed time to castration resistance vs placebo in the overall, high- and low-volume disease populations (median, NR vs 11.4 months, NR vs 8.3 months and NR vs 18.5 months, respectively; all p<0.0001).⁶

Apalutamide is well tolerated. In TITAN, the most common treatment-emergent AE (TEAE) of any grade was skin rash (24.4 percent vs 8.3 percent in apalutamide vs placebo arm), which was also the most common grade 3–4 TEAE (2.9 percent vs 0.6 percent).⁵ Fractures and falls were AEs of interest, but their occurrence was comparable between the apalutamide and placebo groups (all grades: 6.1 percent vs 4.2 percent and 4.6 percent vs 6.8 percent; grade 3–4: 1.5 percent vs 0.5 percent and 0.7 percent vs 0.6 percent, respectively).⁵

Our patient, who presented with high-volume mCSPC and rectal bleeding from tumour erosion, was in need of a reliable treatment after orchiectomy that would provide rapid symptom relief and sustained disease control and, ultimately, improve PFS and OS. Notably, before the introduction of ARIs, patients with mCSPC treated with ADT alone would develop castration resistance within 2–3 years, at which point duration of response to any newly initiated ARI would become very limited.^7,8 Given the narrow window of opportunity, apalutamide was initiated immediately after our patient’s orchiectomy.

Based on our clinical experience, apalutamide is a good option among ARIs because of its predictable efficacy and the rapidity and consistency of observed response, which are especially relevant in high-volume disease. For the above elderly patient, apalutamide was also preferred over chemotherapy because of its favourable safety and tolerability profile.⁹ Although dizziness, falls and resulting fractures have been a concern with ARIs, they have not been observed in apalutamide-treated patients in our clinical practice, making it a suitable option for older patients.^10,11 Skin-related AEs are common with apalutamide, but they are usually mild and manageable with antihistamines and emollients, and they tend to subside after a few months.^3,5 Most of our patients can tolerate the full dose of apalutamide without dose reductions or interruptions.

In this case of an elderly patient with symptomatic, high-volume mCSPC, apalutamide after orchiectomy produced rapid radiological, biochemical and clinical response that has been sustained for nearly 2 years to date, with no sign of disease progression or major AEs.