Prolonged biochemical response after discontinuation of orteronel (TAK-700) in a patient with metastasized castration-resistant prostate cancer

A 73-year-old man, was diagnosed with a T3N1M1a adenocarcinoma of the prostate, Gleason 4 + 4, with iliacal and paraaortic lymph node involvement and an initial PSA of 778 ug/l. Other laboratory results including creatinin, hemoglobin level, LDH and alkalic phosphatase were normal and there was no evidence of bone metastasis. Palliative therapy with busereline, a Gonadotropin releasing hormone (GnRH) agonist was initiated. A biochemical response occurred with a PSA nadir of 23, 16 months after the initiation of androgen deprivation therapy. Castrate refractory disease was diagnosed with a consistent rise in PSA 26 months after diagnosis, but the patient was still asymptomatic. After 14 months of watchful waiting during the castrate refractory state, radiological evaluation was performed due to a shortening in PSA doubling time, although he was still asymptomatic. Multiple bone metastases were detected and PSA had risen to 286 ug/l with a normal alkaline phosphatase at that moment. The patient decided to participate in a double blind, placebo-controlled trial of prednisone with or without orteronel. After the study was closed, deblinding of the study learned that he had been randomized to receive 400 mg orteronel twice daily, together with 5 mg of prednisolone twice daily. Three months after the start of therapy a biochemical response was noted with a decline in PSA to 4.8 ug/l, which decreased further below 1.0 ug/l in May 2012, which was nine months after the start of the treatment. However, after 17 months of orteronel therapy, the patient developed symptoms of severe fatigue (grade 4 CTC AE). The prostate cancer was still in regression (with a PSA of 0.1 ug/l). Thorough physical, laboratory and cardiopulmonary evaluation ruled out non-treatment-related causes for these symptoms. Adrenal insufficiency was ruled out as explanation for the severe fatigue, as ACTH and corticosterone levels were not elevated during the orteronel treatment. The treatment with orteronel and prednisone was interrupted to evaluate whether the symptoms were attributable to the novel agent. Rapidly afterwards recovery started and he fully recovered after two months of drug interruption. In this time frame PSA remained stable on 0.1 ug/l. The orteronel was rechallenged at a 50% dose (200 mg twice daily and prednisone once daily 5 mg), but the symptoms re-occurred within four weeks of treatment. The patient did not want to continue the study medication, therefore the study medication (orteronel and prednisone) was stopped in April 2013 and no other systemic therapy was started. Again after dechallenge, he recovered from the severe fatigue, while PSA levels in the meanwhile became undetectably low (50.04 ug/l) and remained at that level during a prolonged period of time. A first PSA increase to 0.3 ug/l was seen 14 months after discontinuing orteronel permanently. The PSA levels from time of diagnosis until now are depicted in Figure 1. Testosterone at baseline was compatible with the castrate refractory state, however, during therapy with orteronel, there was a further decrease from baseline with about 98% (from 0.3207 to 0.006934 nmol/L). At the end of treatment when orteronel was discontinued for several weeks, the testosterone already increased (0.0659 nmol/L). Regretfully, sensitive testosterone measurements beyond the trial are lacking, but most likely it further increased back to baseline. During treatment, there was also a decline in dehydroepiandrosterone sulfate (DHEAS) and cortisol levels, which similar to testosterone levels, increased already after the discontinuation of orteronel for several weeks. An overview of the hormone levels and number of circulating tumor cells during the study is shown in Table 1. Enumeration of circulating tumor cells was performed in 7.5 ml blood and a CTC count of 3 was found at baseline, while in the four follow-up samples after two, four, six and nine months of therapy the CTC count was zero (Table I). Radiological evaluations were performed at a regular basis during the trial and in comparison to baseline the number of bone metastases declined from six to two on the bone scan two months after initiation of orteronel and no further changes were seen during therapy. Since the initiation of orteronel 39 months have elapsed and the patient is still asymptomatic with no necessity to perform radiological evaluation after discontinuing orteronel. In addition to PSA levels and radiological evaluations, evaluation of hemoglobin, LDH and alkalic phosphatase levels, were normal during the treatment with orteronel and after discontinuation of the study medication indicating no clinical evidence for disease progression.