An elderly patient with metastatic CRPC treated with a new-generation androgen receptor inhibitor

Presentation and initial treatment

A 76-year-old patient was referred to a urologist with the finding of raised prostate-specific antigen (PSA; 10.5 µg/L) in 2007. Prostate biopsy confirmed the diagnosis of prostate cancer with a Gleason score of 8 (4+4).

A bone scan in April 2007 found a metastatic bone lesion in the skull compatible with skull metastasis. The patient was therefore managed with bilateral simple orchidectomy (BSO) alone, performed in August 2007, which resulted in good response with a nadir PSA of 1.2 µg/L achieved in August 2008. However, with time, he developed gradual PSA rebound and was started on flutamide in January 2011 when his PSA reached 12.4 µg/L.

Initial biochemical response to flutamide was good, with a nadir PSA of 0.3 µg/L achieved by July 2011. Subsequently, there was again gradual rebound of disease, with flutamide eventually withdrawn in February 2014 when PSA was 12.5 µg/L.

No response to androgen withdrawal was achieved, and the patient’s PSA rose to 27.7 µg/L by May 2014. At the age of 83 years, he was deemed not physically fit for chemotherapy.

He was started on prednisolone and denosumab in June 2014 for castration-resistant prostate cancer (CRPC), which resulted in a temporary drop in nadir PSA to 4.4 µg/L by June 2015. However, denosumab treatment was complicated by osteonecrosis of the jaw, necessitating surgical debridement in September 2015 and discontinuation of denosumab. His PSA also rebounded to 6.6 µg/L by September 2015. He was, however, continued on prednisolone for another 9 months until June 2016, when his PSA reached 14 µg/L.

Enzalutamide for CRPC

The patient then joined an enzalutamide subsidy programme offered by a charity organization. At the age of 85 years with an ECOG performance score of 2 at the time, he had no contraindications to the drug and had no history of seizure, heart disease or hypertension. Enzalutamide was started in July 2016. Bone scan done at that juncture showed no active bone metastases.

Subsequently, the patient developed hypertension with an office blood pressure (BP) of 184/89 mm Hg and home systolic BP consistently above 160 mm Hg. Bilateral leg oedema with cellulitis was also noted. Enzalutamide was therefore withheld in September 2016, and the patient was given amlodipine for hypertension and a course of antibiotic for cellulitis. With his PSA dropping to 3 µg/L by October 2016, enzalutamide was planned to be withheld for 2 months to allow recovery from cellulitis.

However, the patient’s PSA quickly rebounded to 10 µg/L in November 2016. The cellulitis had resolved and BP was under control. Enzalutamide was therefore resumed in November 2016 under close monitoring.

The patient has since tolerated enzalutamide well, with BP well controlled with antihypertensive therapy from the family medicine clinic. There has been no recurrence of leg cellulitis. PSA levels decreased rapidly to pre-rebound levels and remained low, reaching a nadir of 2.1 µg/L in January 2017.

Subsequently, the patient’s PSA gradually drifted upwards, reaching 4.1 µg/L in January 2018 and 5.2 µg/L in June 2018. Biochemical progression was discussed with the patient and his family, who were keen to continue treatment as enzalutamide was now well tolerated and the patient remained asymptomatic.

A follow-up bone scan was scheduled for November 2019. The patient experienced no bone pain, while his systolic and diastolic BP remained at 130–140/60–70 mm Hg. Currently at the age of 88 years, he is able to walk independently with a stick.

He was last seen in May 2019, with PSA of 10.3 µg/L. He opted to continue treatment and remained asymptomatic and well as of June 2019.

The patient’s PSA trend over time is shown in the figure below. (Figure)

Discussion

Enzalutamide is a new-generation androgen receptor (AR) inhibitor that targets several steps in the AR signalling pathway, including binding of androgen, nuclear translocation of AR complex, and DNA binding.¹ Unlike the older-generation bicalutamide, enzalutamide does not have partial agonist activity.¹

Enzalutamide’s superiority over older antiandrogens has been established in the TERRAIN and STRIVE studies.^2,3 Large randomized studies have confirmed the efficacy of enzalutamide in advanced CRPC in both chemotherapy-naïve (PREVAIL) and post-chemotherapy settings (AFFIRM).^4,5

Our case demonstrates a disease that ran a rather slow clinical course, with a 3-year interval before initiation of first-generation antiandrogen after BSO, and continuation of first-generation antiandrogen for almost 2.5 years before switching therapy. There was a 9-year interval from the diagnosis of metastatic disease to the initiation of enzalutamide.

Hypertension and peripheral oedema are both recognized adverse effects (AEs) of enzalutamide, occurring in 13 percent and 11 percent of patients, respectively, in the PREVAIL study. In our patient, these AEs were successfully controlled and full-dose enzalutamide was resumed with no further problem. Fatigue, the most common (36 percent) AE of enzalutamide, was not reported by our patient.

Consistent with results of clinical trials, time to PSA progression (25 percent increase in nadir PSA with absolute increase of ≥2 µg/L) in our patient was 18 months. However, upon temporary treatment interruption (for 2 months), PSA rebound was extremely rapid: from 3 µg/L to 10 µg/L within 1 month.

This patient opted to continue enzalutamide treatment despite biochemical progression. During this time, his PSA doubling remained relatively slow. More importantly, he tolerated the treatment well and still remained asymptomatic for almost 1.5 years after biochemical failure.

Conclusion

Our case illustrates the efficacy of enzalutamide after treatment failure with flutamide and prednisolone. The time to progression is consistent with that reported in clinical trials. AEs encountered were reversible and full-dose treatment was resumed with good tolerability.

The patient opted for continued treatment beyond biochemical progression. He experienced continued rise in PSA with relatively slow doubling, and remained asymptomatic 1.5 years after biochemical failure. While temporary withholding of enzalutamide early in the course of treatment led to very rapid rebound of PSA, this was reversible upon resumption of treatment.