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Metabolic and Prostate-Specific Antigen Response After Abiraterone Acetate Withdrawal: A New Clinical Scenario for Castration-Resistant Prostate Cancer?

Clinical Genitourinary Cancer, 4, 11, pages e10 - e14

Editor's comments

Although so far there is only case based evidence, this may be an interesting phenomenon.

 

 

  • The availability of new drugs for castration-resistant prostate cancer patients might open new clinical scenarios that are unexpected.
  • The withdrawal syndrome is a well known occurrence after antiandrogen therapy but is not described with use of the new drugs that act on androgen metabolism. It is usually unable to produce an instrumentally detectable improvement of the disease.
  • We describe 2 cases of patients with castration-resistant, metastatic prostate cancer who experienced an abiraterone acetate (AA) withdrawal syndrome, and achieved a metabolic response.
  • We obtained serial prostate-specific antigen (PSA) measurements and choline positron emission tomography/computed tomography (cPET/CT) scans to assess the patients' response to AA withdrawal.
  • The described patients stopped taking AA because of lack of biochemical response and progression occurrence visualized on cPET/CT scans. Before the start of new treatment, their PSA levels decreased and they remained using no therapy.
  • After 3 months, we observed a progressive additional PSA reduction and a repeated cPET/CT scan revealed an improvement.
  • This is the first report of a long-term withdrawal syndrome and a metabolic response after AA withdrawal.
  • It seems to represent a rare new clinical scenario that might delay the introduction of additional treatment lines.
  • Our findings suggest that it might also lead to a measurable improvement in disease.

Clinical Practice Points

Introduction

Patients with hormone-sensitive prostate cancer who show increasing prostate-specific antigen (PSA) levels during a complete androgen blockade (CAB) might benefit from the withdrawal of antiandrogen therapy. This well known phenomenon of antiandrogen withdrawal response is characterized by a new decrease in PSA levels. Retrospective studies have described antiandrogen withdrawal response in a minority of patients undergoing antiandrogen withdrawal, 1 and 2 prospective phase III trials have tested this strategy together with other medical manipulation and confirmed its limited efficacy.2 and 3 Moreover, like that of other second-line hormonal strategies, the use of antiandrogen withdrawal has been superseded because of the docetaxel activity in patients with castration-resistant prostate cancer.4 and 5 It has recently been demonstrated that 2 new drugs that act on androgen metabolism are active after treatment with docetaxel has failed: abiraterone acetate (AA), which impairs androgen production by inhibiting cytochrome P-450c17α -hydroxylase (CYP17), 6 and enzalutamide, which acts by means of a triple androgen receptor blockade. 7 These new drugs are rapidly entering clinical practice and their widespread use has allowed physicians to observe new scenarios such as AA withdrawal response that were not previously reported.

We describe 2 patients in whom the discontinuation of AA because of progressive disease was followed by withdrawal response with an improvement measured using positron emission tomography (PET) scan.

Case 1

This 72-year-old patient was diagnosed as having prostate adenocarcinoma (Gleason score 7: 4+3) with synchronous bone metastases in October 2008. The initial CAB was withdrawn because of progressive disease without any subsequent response, and so he was then treated with eight 3-week docetaxel courses, which led to a short-lasting partial response. In June 2012, the patient showed clear biochemical progression (his PSA levels increased from 26 to 173 ng/mL), and metabolic progression with the appearance of new lesions revealed by means of choline PET/computed tomography (cPET/CT). AA was therefore started at the standard dose of 1000 mg/d in combination with prednisone (5 mg twice daily). After 3 months, there was no decrease in PSA levels, which actually slightly increased to 184 ng/mL. A repeat cPET/CT scan revealed a considerable increase in standardized uptake value (SUV) (ΔSUVmax = +79%), with the appearance of 6 new bone lesions and 1 liver lesion (20 mm on CT scan), and so AA and concomitant prednisone were discontinued. Two weeks later, before the start of new treatment, his PSA levels decreased to 79 ng/mL and, 3 months later, to 48 ng/mL, when a cPET/CT scan reassessment revealed a very large reduction in SUV (ΔSUVmax = −74%) and the disappearance of the liver lesion (on PET and CT scans). Four months after this discontinuation, the patient is still not being treated, except for the administration of the luteinizing hormone-releasing hormone (LHRH) agonist, which was never stopped.

Case 2

This 77-year-old patient was diagnosed as having a stage T3bN0M0 prostate adenocarcinoma (Gleason score 6: 3+3) in 1995. He underwent external radical radiotherapy at a dose of 76 Gy and remained disease-free until 1997, when he experienced a biochemical failure. From October 1997 to December 2008, his metastasis-free disease was managed with intermittent LHRH agonist therapy. In December 2008, we observed bone progression and proposed bicalutamide, which led to a transient biochemical response until August 2009. At this time, bone scan progression and an increase in PSA levels suggested progressive disease, and so antiandrogen withdrawal was attempted without success. The patient was then treated with 3 courses of weekly docetaxel, which led to a short-lasting partial response. In August 2012, by which time the patient's PSA levels had increased to 179 ng/mL, a cPET/CT scan showed clear progression with the appearance of new bone and nodal lesions. AA was started at the standard dose of 1000 mg daily in combination with prednisone (5 mg twice daily), and the LHRH agonist treatment was continued. After 3 months, there was no decrease in PSA levels, which actually slightly increased to 192 ng/mL, and a repeated cPET/CT scan showed a mixed metabolic response with a considerable increase in the SUV of some lesions (with extension of uptake area) and a slight reduction in others (ΔSUVmax = −13%). AA treatment and concomitant prednisone were stopped and, 2 weeks later, the patient's PSA levels decreased to 62 ng/mL and, 3 months later, to 16 ng/mL. At this time, a cPET/CT scan reassessment showed the persistence of the known bone and nodal lesions but a good metabolic response (ΔSUVmax = −35%), and so the therapeutic holiday was continued (with continuation of treatment with the LHRH agonist).

Discussion

To the best of our knowledge, this is the first report of a long-term withdrawal response and an improvement measured using PET scan after AA withdrawal.

The 2 patients described in this report were considered to be resistant to AA: in the first case, a slight increase in PSA levels and metabolic progression on cPET/CT scan were observed after 3 months of AA treatment and, in the second, although the overall SUV remained substantially stable, the considerable increase observed in some lesions and the extension of uptake area was considered as indicating resistance. AA therapy was therefore stopped and a possible further line of treatment was sought. Surprisingly, 2 weeks after the discontinuation of AA, there was a very large decrease in PSA levels in both cases and it was decided to delay any further treatment.

The AA withdrawal response continued over time and was confirmed by the fact that a cPET/CT scan after 3 months showed a clear metabolic response. For example, in the first patient, the right femur head (which did not have any metabolic accumulation at the start of AA therapy [ Figure 1 A]) showed 3 new lesions after 3 months of treatment ( Figure 1 B), all of which showed a considerable reduction in SUV 3 months after treatment discontinuation ( Figure 1 C). More significantly, the patient's liver (which was free of metastases before the start of AA therapy [ Figure 2 A]) developed a sure lesion (SUV 20) after 3 months of treatment ( Figure 2 B), but returned to being lesion-free after the treatment was stopped ( Figure 2 C). In the second case, the multiple thoracic spine lesions observed at the start of AA therapy ( Figure 3 A), and which showed opposite SUV changes at its end ( Figure 3 B), either decreased further or showed an SUV reduction after the worsening at AA stop ( Figure 3 C).

gr1

Figure 1 Case 1. Right Femur Head Changes Over Time on cPET/CT Scan (A) at AA Treatment Start; (B) at AA Treatment End; (C) 3 Months After AA Treatment End Abbreviations: AA = abiraterone acetate; cPET/CT = choline positron emission tomography/computed tomography.

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Figure 2 Case 1. Liver Changes Over Time on cPET/CT Scan (A) at AA Treatment Start; (B) at AA Treatment End; (C) 3 Months After AA Treatment End Abbreviations: AA = abiraterone acetate; cPET/CT = choline positron emission tomography/computed tomography.

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Figure 3 Case 2. Thoracic Spines Changes Over Time on cPET/CT Scan (A) at AA Treatment Start; (B) at AA Treatment end; (C) 3 Months After AA Treatment end Abbreviations: AA = abiraterone acetate; cPET/CT = choline positron emission tomography/computed tomography.

Only 1 previous case of AA withdrawal response has been described in the literature. 8 This patient received AA after 2 chemotherapy lines and had failed to achieve a good biochemical response (a 12% reduction in PSA levels) although 18-fluorodeoxyglucose PET and cPET (ΔSUVmax = −37%) revealed a partial metabolic response. The patient stopped receiving AA after 4 months because of clinical worsening (increasing pain) and an increase in PSA levels. A major PSA response (52% reduction) was observed 1 month after AA withdrawal and, 3 months after discontinuing AA, the patient experienced definite clinical and biochemical progression. Unfortunately, the PET scan evaluation was not repeated at the time of AA discontinuation or during the withdrawal response.

More recently, preliminary results on 66 patients treated with AA showed a transient (until 11.5 weeks) major PSA decrease in only 4 patients with a potential clinical benefit in 2 cases: the authors concluded that AA withdrawal response is an event of minor magnitude and short-term. 9

The biological basis of antiandrogen withdrawal response is still unclear, although the presence of androgen receptor mutations is the most frequently hypothesized mechanism 10 because they could explain the paradoxical stimulatory effect that flutamide exposure can have on the growth of the LNCaP prostate cancer cell line.11 and 12

Abiraterone acetate mainly acts by inhibiting CYP17, a rate-limiting enzyme of steroidogenesis, 13 but it has been clearly shown that androgen receptors play a key role in determining the degree of sensitivity/resistance to AA,14, 15, and 16 and so androgen receptor mutations might play a role in AA withdrawal response. Furthermore, mutated androgen receptors in prostate cancer cells after the failure of androgen ablation therapy might take on a high-affinity cortisol/cortisone receptor function, and the growth of these cells might be stimulated by circulating glucocorticoids. 17 Considering this, it cannot be excluded that AA withdrawal response might be more related to the discontinuation of corticosteroid than the discontinuation of AA.

Conclusion

Although a full clinical overview of AA withdrawal response requires further observations and biological analyses, it seems to represent a rare new clinical scenario that might delay the introduction of further treatment lines. Our findings suggest that it might also lead to a measurable improvement in disease.

Disclosure

The authors have stated that they have no conflicts of interest.

References

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  • 2 E.J. Small, S. Halabi, N.A. Dawson, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-1033 Crossref.
  • 3 A.O. Sartor, C.M. Tangen, M.H. Hussain, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008;112:2393-2400 Crossref.
  • 4 D.P. Petrylak, C.M. Tangen, M.H. Hussain, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520 Crossref.
  • 5 I.F. Tannock, R. de Wit, W.R. Berry, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512 Crossref.
  • 6 J.S. de Bono, C.J. Logothetis, A. Molina, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005 Crossref.
  • 7 H.I. Scher, K. Fizazi, F. Saad, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197
  • 8 H. Gauthier, G. Bousquet, D. Pouessel, et al. Abiraterone acetate withdrawal syndrome: does it exist?. Case Rep Oncol. 2012;5:385-387 Crossref.
  • 9 L. Albiges, E. Auclin, B. Rousseau, et al. Is there a withdrawal syndrome with abiraterone acetate (AA)? (abstract 89). J Clin Oncol. 2013;:31
  • 10 G. Han, G. Buchanan, M. Ittmann, et al. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci U S A. 2005;102:1151-1156 Crossref.
  • 11 G. Wilding, M. Chen, E.P. Gelmann. Aberrant response in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate. 1989;14:103-115 Crossref.
  • 12 J. Veldscholte, C. Ris-Stalpers, G.G. Kuiper, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990;173:534-540 Crossref.
  • 13 M. Jarman, S.E. Barrie, J.M. Llera. The 16,17-double bond is needed for irreversible inhibition of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) and related steroidal inhibitors. J Med Chem. 1998;41:5375-5381 Crossref.
  • 14 C. Cai, S. Chen, P. Ng, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71:6503-6513 Crossref.
  • 15 E.A. Mostaghel, B.T. Marck, S.R. Plymate, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011;17:5913-5925 Crossref.
  • 16 E. Efstathiou, M. Titus, D. Tsavachidou, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol. 2012;30:637-643 Crossref.
  • 17 X.Y. Zhao, P.J. Malloy, A.V. Krishnan, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6:703-706

Footnotes

1 Medical Oncology Department, Santa Chiara Hospital, Trento, Italy

2 Nuclear Medicine Department, Santa Chiara Hospital, Trento, Italy

Address for correspondence: Orazio Caffo, MD, Medical Oncology Department, Santa Chiara Hospital, Largo Medaglie d'Oro, 38100 Trento, Italy Fax: +390461903364