Fall In Prostate-specific Antigen Research Articles

Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Phase I/II Trial of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer (LuPIN)

BackgroundTrials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. ObjectiveTo evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. Design, setting, and participantsThirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. InterventionScreening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1–10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. Outcome measurements and statistical analysisAdverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. Results and limitationsFifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median –74%; 95% confidence interval [CI] 76–97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45–77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8–9.2) and median overall survival was 17.1 mo (95% CI 6.5–27.1). ConclusionsNOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. Patient summaryAddition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617.

Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis

BackgroundDeclines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. ObjectiveTo evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. Design, setting, and participantsThis was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Outcome measurements and statistical analysisAssociation with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results and limitationsWe identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4wk, and 948 at both 4 and 12wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio=0.57; 95% CI=0.48–0.67; p<0.001). PSA4w30 strongly correlated with PSA12w30 (ρ=0.91; 95% CI=0.90–0.92; p<0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4wk had a PSA12w30 (1% of the overall population). ConclusionsPSA changes in the first 4wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Patient summaryProstate-specific antigen changes at 4wk after abiraterone/enzalutamide treatment are important to determine patients’ outcome and should be taken into consideration in clinical practice.

Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low- vs. high-risk of radiographic progression: An analysis of COU-AA-302.

Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. We accessed data for men with chemotherapy-naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone-only disease and a ≥50% fall in PSA was 93% (95% confidence interval [CI] 87-96) at six months and 80% (95% CI 72-86) at 12 months. In contrast, the probability of RPFS for men with bone and soft tissue metastasis and <50% fall in PSA was 55% (95% CI 41-67) at six months and 34% (95% CI 22-47) at 12 months. These findings should be externally validated. Patients with chemotherapy-naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized.

PD10-07 PREDICTORS OF RADIOGRAPHIC PROGRESSION IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH ABIRATERONE: RETROSPECTIVE ANALYSIS OF COU-AA-302

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I1 Apr 2018PD10-07 PREDICTORS OF RADIOGRAPHIC PROGRESSION IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH ABIRATERONE: RETROSPECTIVE ANALYSIS OF COU-AA-302 Lisa Martin, Shabbir Alibhai, Maria Komisarenko, Narhari Timilshina, and Antonio Finelli Lisa MartinLisa Martin More articles by this author , Shabbir AlibhaiShabbir Alibhai More articles by this author , Maria KomisarenkoMaria Komisarenko More articles by this author , Narhari TimilshinaNarhari Timilshina More articles by this author , and Antonio FinelliAntonio Finelli More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.617AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radiographic imaging is used to monitor disease progression for men with metastatic castrate resistant prostate cancer (mCRPC) to make decisions about their treatment. Information about the optimal frequency of imaging is important because imaging is costly and access may be limited. We sought to identify predictors of radiographic progression that could be used in clinic to inform the frequency of imaging for men with mCRPC. METHODS We accessed data for men with chemo-naive mCRPC in the abiraterone treatment group of a phase III randomized trial (COU-AA-302) (n=546) through the Yale University Open Data Access Project. The outcome measure was time from randomization to radiographic progression in bone and/or soft tissue (n=301 events). We used univariable and multivariable Cox proportional hazards modelling to identify predictors of time to progression. We then divided the subjects into 6 risk strata based on the 2 variables most strongly associated with progression and estimated the probability of radiographic progression free survival (RPFS) at 6 and 12 months after starting abiraterone. RESULTS The median time to radiographic progression was 16.6 months (95% confidence interval (CI) of 14.4 to 19.3 months). A model containing baseline variables (extent of disease, ECOG status, pain, prostate specific antigen (PSA), lactate dehydrogenase, alkaline phosphate (ALP) and albumin) and change in PSA and ALP at 8 weeks had a concordance statistic of 0.71. Extent of disease at baseline and change in PSA at 8 weeks were the strongest independent determinants of RPFS. The probability of RPFS for men with bone only disease at baseline and a >= 50% fall in PSA (32% of all subjects, lowest risk stratum) was 93% (95% CI 87 to 96) at 6 months and 80% (95% CI 72 to 86) at 12 months. In contrast, the probability of RPFS for men with bone and soft metastasis at baseline and < 50% fall in PSA (13% of all subjects, highest risk stratum) was 55% (95% CI 41 to 67) at 6 months and 34% (95% CI 22 to 47) at 12 months. CONCLUSIONS Patients with chemo-naive mCRPC treated with abiraterone can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables. These results suggest that the imaging schedule for these patients could be individualized. This finding should be externally validated, and examined with other treatments, and may ultimately lead to more efficient use of imaging in men with mCRPC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e230 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Lisa Martin More articles by this author Shabbir Alibhai More articles by this author Maria Komisarenko More articles by this author Narhari Timilshina More articles by this author Antonio Finelli More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

Objective. The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting. Material and methods. Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test, Mann–Whitney U test and linear regression model were used to test for differences in PSA response. Results. All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was –12% (range –56% to 76%), while the median best PSA response was –22% (–76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months. Conclusions. Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?

Abiraterone and docetaxel are both approved treatments for men with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone pre-docetaxel is currently undergoing evaluation in a phase III study. In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling. We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy. We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone, using Prostate Cancer Working Group and radiological criteria. Of the 54 patients treated with abiraterone, 35 subsequently received docetaxel. Docetaxel resulted in a prostate-specific antigen (PSA) decline of ≥50% in nine patients [26%, 95% confidence interval (CI) 13% to 43%], with a median time to PSA progression of 4.6 months (95% CI 4.2% to 5.9%). PSA declines ≥30% were achieved by 13 patients (37%, 95% CI 22% to 55%). The median overall survival was 12.5 months (95% CI 10.6-19.4). All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone-refractory were also docetaxel-refractory (N = 8). In the 24 patients with radiologically evaluable disease, partial responses were reported in four patients (11%), none of whom were abiraterone-refractory. The activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone-refractory patients.

Gonadotropin-releasing hormone/human chorionic gonadotropin β based recombinant antibodies and vaccines

Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) are unique targets for the control of fertility. Immunological approaches to neutralizing these hormones have additional utility in cancer treatment. Vaccines have been developed against both GnRH and hCG and these have undergone Phase I/II clinical trials documenting their safety, reversibility and efficacy. The heterospecies dimer hCG vaccine prevented pregnancy in women of proven fertility without impairment of ovulation or derangement of menstrual regularity and bleeding profiles. The protective threshold of antibody titers to achieve efficacy was determined in these first-ever trials. Recently, a recombinant vaccine against the beta subunit of hCG linked to the B subunit of heat labile enterotoxin has been made and expressed as a glycosylated conjugate in Pichia pastoris. Experiments indicate its ability to generate antibodies above the protective threshold in all immunized Balb/c mice. Ectopic expression of hCG/hCGbeta is observed in many advanced stage cancers of various origins. A chimeric high affinity and specific recombinant antibody against hCGbeta linked to curcumin kills hCGbeta expressing T lymphoblastic leukemia cells without any deleterious effect. Several synthetic and recombinant vaccines have been developed against GnRH. These reduce serum testosterone to castration levels causing atrophy of the prostate. Three Phase I/II clinical trials conducted in India and Austria have shown that these vaccines elicit non-surgical reduction of testosterone, a fall in prostate specific antigen and clinical improvement of prostate carcinoma patients. A multimer recombinant vaccine against GnRH has high efficacy for sterilization of pigs and other animals.

Prostate-Specific Antigen: A Misused and Maligned Prostate Cancer Biomarker

Prostate-Specific Antigen: A Misused and Maligned Prostate Cancer Biomarker

7α‐Methyl‐19‐Nortestosterone (MENT) vs Testosterone in Combination With Etonogestrel Implants for Spermatogenic Suppression in Healthy Men

Testosterone with a progestogen can suppress spermatogenesis for contraception. The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) may offer advantages because it is resistant to 5alpha-reduction and is therefore less active at the prostate. This study aimed to investigate MENT implants in combination with etonogestrel on spermatogenesis, gonadotropins, and androgen-dependent tissues in comparison with a testosterone/etonogestrel regimen. Healthy men (n = 29) were recruited and randomized to receive 2 etonogestrel implants with either 600-mg testosterone pellets repeated every 12 weeks or 2 MENT implants for up to 48 weeks. Testosterone concentrations in the testosterone group remained in the normal range. Subjects with 2 MENT implants showed peak MENT levels at 4 weeks with testosterone concentrations of 2 nmol/L. Sperm concentrations fell rapidly to less than 1 x 10(6)/mL at 12 weeks in 8 of 10 subjects in the MENT group and 13 of 16 subjects in the testosterone group with equally suppressed gonadotropins. Thereafter, suppression was not maintained in the MENT group, and 6 men noted loss of libido. Fourteen men completed 48 weeks of testosterone treatment, and all became azoospermic. Hemoglobin concentrations rose, and high density lipoprotein-cholesterol (HDL-C) fell in both groups. The MENT group showed a fall in prostate-specific antigen with no change in bone mass. MENT with a progestogen can achieve rapid suppression of spermatogenesis similar to testosterone, but this promising result was not sustained due to a decline in MENT release from the implants. This dose of testosterone, compared with previous studies using a lower dose with a higher dose of etonogestrel, had nonreproductive side effects without any increase in spermatogenic suppression. These data indicate the importance of the doses of progestogen and testosterone for optimum spermatogenic suppression while minimizing side effects.

An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer

The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4–184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy.

Prostate-specific antigen in prostate cancer: A case study in the development of a tumor marker to monitor recurrence and assess response

The serum marker known as prostate-specific antigen (PSA) has established itself as the most important tool for the early detection of prostate cancer. However, more recent data indicate that (post-treatment) PSA and PSA kinetics can be used to predict the outcome of a variety of therapeutic interventions including radical prostatectomy, radiation therapy, androgen deprivation, and treatment of hormone-refractory prostate cancer. PSA recurrence after radiation therapy is now accepted as a harbinger of developing metastatic disease. The American Society for Therapeutic Radiation Oncology (ASTRO) consensus definition is the most widely accepted definition of failure after radiation therapy. Rather than using a specific PSA cutoff, three consecutive PSA rises was felt to be a more reliable indicator of biochemical failure. The PSA nadir (the lowest PSA level achieved after therapeutic intervention) also appears to correlate with the likelihood of remaining disease-free. Similarly, a rapid doubling time is a significant predictor of developing distant metastases. The most appropriate definition for biochemical (PSA) failure following radical prostatectomy is usually considered to be a non-zero value. As is the case after radiotherapy, there appears to be a relationship between the rate of rise of the PSA and the risk of distant failure following radical prostatectomy. In patients with metastatic disease, multiple studies appear to indicate that a fall in PSA, however measured, appears to be predictive of improved outcome in prostate cancer patients treated with androgen deprivation. Multiple reports of trials in the treatment of hormone-refractory prostate cancer (HRPC) appear to substantiate the observation that patients who have a greater than 50% decline in PSA have an improved survival. Correlation of PSA declines with other markers of clinical benefit, including clinically significant “subjective” end points such as pain control, have strengthened the argument that a PSA decline can serve as an intermediate endpoint in clinical trials involving HRPC patients. Semin Oncol 29:264-273. Copyright 2002, Elsevier Science (USA). All rights reserved.

Strontium-89 treatment for prostate cancer bone metastases: does a prostate-specific antigen response predict for improved survival?

A review of 50 patients treated with strontium-89 for prostate cancer bone metastases from January 1993-1997 at the Wellington Cancer Centre was undertaken to determine if there was any correlation between changes in prostate-specific antigen (PSA) following treatment and subsequent survival. Thirty cases were evaluable for PSA response. Of these, 14 had a fall in PSA following strontium-89 treatment, and their mean survival was 641 days. The remaining 16 patients did not demonstrate a post-treatment fall in PSA and their mean survival was 275 days. A difference between these two groups in the time to development of new bone symptoms following treatment was also observed. No significant correlation between pretreatment PSA and PSA response was observed. In conclusion, a PSA response following strontium-89 treatment appears to predict for improved survival in patients with bone metastases from carcinoma of the prostate. Further prospective studies are indicated.

Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer.

Fosfestrol tetrasodium (Honvan) is a synthetic oestrogen-based compound. Studies have suggested its use in the treatment of localised, advanced and hormone-refractory prostate cancer. This series of 17 patients with advanced disease documents the response, both subjective and objective, to standard dose intravenous Honvan infusion. Infusions were well tolerated, with no cardiovascular side-effects. Twelve patients received Honvan as de novo therapy, of whom 10 (83%) described subjective improvement and 11 (92%) had objective evidence of improvement, 11 (92%) had documented falls in prostate-specific antigen (PSA) levels. Nine patients received Honvan infusions as secondary treatment for hormone-escaped disease (1 patient received Honvan for a second time and another for a second and third time). Of these, 1 (11%) had a documented fall in PSA; 3 (33%) reported a subjective symptomatic improvement, and 2 (22%) demonstrated objective evidence of improvement. Patients with symptoms from bulk abdomino-pelvic disease seemed to fare better than those with bony metastases. This may suggest a specific indication for Honvan in a subgroup of patients with acute obstructive events of the ureters, urethra or circulatory vessles, in particular its value as a de novo therapy. In those patients who received Honvan as secondary therapy, some response was seen in a third, but overall these patients remained hormone-refractory.

Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome.

The growth of prostate cancer is androgen responsive, and androgen receptor (AR) is thought to play an important role in the development of this cancer. Recently, some reports demonstrated that AR gene mutations were detected in human prostate cancer tissues. We have previously reported that one of eight endocrine therapy-resistant prostate cancer cases showed AR gene mutation [Suzuki et al: J Steroid Biochem Mol Biol 46:759-765, 1993]. To further investigate structural abnormality of the AR in a large number of human prostate cancers, exons B-H encoding DNA-and hormone-binding domains were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products and direct sequencing. Tissues surgically removed from 30 cases of stage B or C prostate cancer and from 22 cases of endocrine therapy-resistant cancers obtained at autopsy were used in the study. Three out of 22 cancer death cases (14%) revealed AR gene mutations, one of which contained two different mutations-exon D in cancerous prostate and exon H in metastatic tissues. In the other two cases, AR gene mutations in exon H were found in metastatic tissues. All three cases in metastatic tissues showed the same mutation at codon 877 (877Thr-->Ala). In stage B or C cancer tissues and the other cancer death samples, no AR mutation was detected. The mutation in exon H was identical to that reported in a human prostate cancer cell line, LNCaP. These results indicate that AR gene mutation scarcely occurs in the early stage of prostate cancer and that the mutation is found in relation to endocrine therapy resistance. Two patients with an AR gene mutation at codon 877 revealed a remarkable fall in prostate-specific antigen after withdrawal of antiandrogen. Data on the other case were not available. These results indicate that a codon 877 mutation in the AR gene in advanced prostate cancer evokes the antiandrogen withdrawal syndrome. To our knowledge, this report is the first description of relationship between an AR mutation at codon 877 and the antiandrogen withdrawal syndrome.

The source of pretreatment serum prostate-specific antigen in clinically localized prostate cancer—T, N, or M?

Purpose : Prostate-specific antigen (PSA) is an important marker for prostate cancer and has been shown to be secreted from the primary tumor and from metastases. However, the relative contribution of the primary and micrometastatic disease to the serum level of PSA in patients with clinically localized disease has not been delineated. This study addresses the source of pretreatment serum PSA in patients with clinically localized disease. Methods and Materials : The fall in serum PSA level following radical prostatectomy (280 patients; 105 T1, 165 T2, 10 T3) or definitive radiotherapy (427 patients; 122 T1, 147 T2, 158 T3/T4) was analyzed with the assumption that any fall in PSA following local treatment reflects the fraction of PSA produced in the prostate and its primary tumor. Results : Serum PSA level became undetectable in 277 of the 280 (99%) patients within 6 months of radical prostatectomy. The three patients who did not achieve undetectable levels had postsurgical values ≤ 0.9 ng/ml. Following definitive radiotherapy, nadir serum PSA values were between ≤ 0.3 and 20.3 ng/ml, with mean and median values of 1.9 and 1.2 ng/ml, respectively. Nadir PSA was undetectable in 52 patients (12%). Four patients' PSA did not fall, but rose from the start, and each developed metastatic disease within 9 months, and in each metastases appeared to contribute to pretreatment serum PSA. In the remaining patients, the maximal factor by which PSA fell to its nadir was higher the higher the pretreatment PSA level. We present arguments that this is most consistent with the hypothesis that virtually all detectable pretreatment serum PSA derives from the primary tumor. Confirmatory evidence that little of the pretreatment serum PSA came from metastases was obtained by extrapolating the rising PSA profile in 97 patients back to pretreatment time. Back-extrapolated PSA contributed a mean of 7% and a median of 5% to the pretreatment serum value. Because such back-extrapolated values estimate the potentially maximal micrometastatic contribution, metastatic disease at diagnosis contributes little to pretreatment serum PSA. Conclusion : In patients with clinically localized prostate cancer, putative micrometastatic disease contributes negligibly to the pretreatment serum PSA level even when the latter is high. Most likely such patients, when they have metastases, have a very low metastatic burden.

The serum prostate-specific antigen level three months after radiotherapy for prostate cancer: an early indicator of response to treatment

A total of 347 patients with stages A2-C adenocarcinoma of the prostate treated with external beam radiotherapy and with pretreatment and 3-month prostate-specific antigen (PSA) levels were studied to evaluate the potential prognostic significance of the fall in PSA concentration from its baseline (PSAB) to its 3-month (PSA3) level. PSA levels fell in 333 patients (96%). With two exceptions, the patients whose PSA level did not fall had low PSAB and remained without evidence of disease. Since PSA levels fall virtually always, the fact that a fall occurs is of no prognostic value. When the magnitude of the fall relative to baseline was examined, patients with the largest falls had the worst outcomes. This paradoxical result was explained by the relationship between PSAB and PSA3. Regression analysis showed that the fall in PSA level was approximately proportional to the cube root of the baseline value. Thus, patients with high PSAB had high falls, but a high PSAB was an ovewhelming predictor for poor outcome. Hence, PSA fall relative to baseline was not a meaningful prognostic factor. The only factor of prognostic value was the absolute PSA3 value. Patients with PSA3 ≤2 ng/ml fared well at 4 years (freedom from relapse, 91%; incidence of rising PSA profile, 20%); patients with PSA3 > 2, but <-10 ng/ml had an intermediate, individually indeterminate outcome (freedom from relapse, 51%; incidence of rising PSA profile, 58%); patients with PSA3 >10 ng/ml can be said to have failed treatment (freedom from relapse, 50%; incidence of rising PSA profile, 90%). Although this analysis is based on short follow-up, it shows that the PSA value at 3 months after radiation provides a remarkably early assessment of response to treatment and the only patients who can be clearly stated to have responded well to treatment are those whose PSA level falls to ≤ 2 ng/ml. The long-term implications of 3-month PSA values await further follow-up.

Update of Monotherapy Trials with the New Anti-Androgen, Casodex (IC1176,334)

Casodex (ICI 176,334) is a non-steroidal anti-androgen, which has a half-life compatible with once-daily oral dosing. In an open, phase II study on 267 patients given Casodex, 50 mg/day, an overall objective response (i.e. partial regression) was seen in 55.5% of patients (146 of 26 3) with a further 15.6% (41 of 263) having stable disease. Two of three randomized, phase III studies conducted with Casodex, 50 mg/day, showed it to be inferior to castration (either medical or surgical) on time to treatment failure and time to progression. A subsequent overview analysis of survival from these three studies showed a statistically significant difference in favour of castration. Prostate specific antigen (PSA) at 3 months correlated well with clinical outcome in the phase III studies of Casodex, 50 mg/day; a greater fall in PSA at 3 months was observed with Casodex, 100 and 150 mg/day, in an open dose-ranging study. As no significant tolerability issues were reported, further investigation of Casodex at these higher doses is in progress. All studies in which Casodex has been investigated have shown it to be a well-tolerated anti-androgen with a good side-effect profile compared with those reported for other available non-steroidal anti-androgens