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`JANSSEN EXHIBIT 2022
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`Wockhardt v. Janssen lPR2016-01582
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`JANSSEN EXHIBIT 2022
`Wockhardt v. Janssen IPR2016-01582
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`396
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`397
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`EFFECTIVE SUSTAINED ANDROGENIC SUPPRESSION WITH
`(D—Nal(2)6), NAFARELIN ACETATE: A NEW INTRANASAL FORQA
`OF LHRH AGONIST.
`Sulpyl Kalash and Mario Eisenberger ,
`Baltimore, MD; Milan Henzl
`and Philip Hoffman , Palo Alto, CA
`(Presentation to be made by Dr. Kalash)
`122
`To test
`the efficacy of an intranasal LHRH agonist,
`patients with previously untreated stage D2 prostate CA were
`randomized on to an ongoing trial comparing (D-Nal(2)6)—LHRH
`(nafarelin acetate, Syntex Research) at a dose of 0.3 mg by
`intranasal spray BID, to DES,
`1 mg p.o. TlD. Effective long term
`testosterone ('1') suppression to limits of detectability was achieved
`with nafarelin. Mean (T) values:—baseline-IJ.8 ng/ml; first week -
`
`6.7ng/ml; week lI-O.3 ng ml and 6 mos-0.2 ng/ml. Mean values with
`DES were:—baseline 4.3 ng/ml; first week-1.5 ng/ml; week 4 — 0.4
`ng/ml and 6 mos - 0.3 ng/ml.
`in patients receiving treatment for
`long periods of time (median follow—up 219 days), no (T) elevations
`were observed after morning nafarelin doses. The major cardio-
`vascular complications (myocardial infarction, pulmonary embolus,
`acute thrombo-phlebitis, deep vein thrombosis, and congestive
`heart failure) requiring early discontinuation of treatment occured
`only on the DES arm. One patient on nafarelin developed mild
`transient epistaxis which did not require treatment modification
`and another was switched to subcutaneous nafarelin due to com-
`pliance problems. Fifty-eight patients have been randomized to
`nafarelin and 64 to DES.
`Similar objective/subjective response
`rates were seen in both arms. With a median F/U of 6 mos (1—14
`mos), 82% and 76% of the nafarelin and DES patients respectively
`continue on treatment without evidence of disease progression.
`Nafarelin has a low incidence of
`toxicity and no major
`compliance problems. Contrary to previous reports on another
`intranasal LHRH agonist, nafarelin produces sustained suppression
`of (T)
`to the limits of detectability. Clinical benefits thus far
`seem comparable to DES and other forms of parenteral LHRH
`analogs.
`lntranasal administration of such compounds should
`enhance their attractiveness for clinical use by circumventing the
`need for daily subcutaneous administration.
`Further patient
`accrual and long term follow-up are needed to determine effect on
`disease free and overall survival.
`
`IN THE MANAGEMENT OF
`(H.D.)
`DOSE
`HIGH
`KETOCONAZOLE
`METASTATIC PROSTATIC CARCINOMA. Frans M.J. Debruyne, Fred
`J. witjes‘
`and
`the members of
`the Dutch
`South—East
`Cooperative Studygroup.
`(Presentation to be mady by Dr.
`Debruyne)
`inhibits testosterone production in
`Ketoconazole H.D.
`both the
`testes
`and adrenals
`and has
`therefore been
`recently advocated for
`the treatment of prostate cancer.
`79 patients
`(pts) with histologically proven metastatic
`carcinoma of
`the prostate were treated with Ketoconazole
`H.D..
`40 pts were untreated,
`18 pts had one hormonal
`treatment and 21 pts had several hormonal therapies before
`starting ketoconazole
`ILD.
`Two
`treatment
`regimes were
`compared: 3 x daily 400 mgr
`(48 pts) and 2x daily 600 mg:
`(31 pts) of a Ketoconazole suspension. RESULTS: Pretreated
`group: Objective response:
`(EORTC criteria) in 60% of the
`pts stable disease and in 40% progression at
`6 months.
`Subjective response (WHO criteria) was seen in 543 of the
`symptomatic patients (36 pts). Untreated group: objective
`response: CR, PR and SD was seen in 29 pts (73%) at
`6
`months
`and
`progression
`in
`11
`pts
`(27‘). Subjective
`improvement occured
`in
`82% of
`the
`symptomatic pts.
`Castration level of
`testosterone was obtained in all
`patients within 2 days. Endocrinologicall
`a
`further
`decrease in testosterone from 35 ng/dl
`(mean +SD)
`to 20
`ng/dl
`(mean + SD) within 2 days was seen in both therapy
`arms.
`(castration level
`30 ngr/dl) Side effects: No
`adrenal
`insufficiency or hepatic toxicity was observed.
`Major
`toxicity signs were gastro—intestinal disturbances
`(nausea—vomiting) which occured in 35% of
`the pretreated
`patients and 26% of the non-pretreated group.
`Conclusion: Ketoconazole E.D.
`is effective
`in
`the
`treatment of patients with prostatic cancer.
`In addition,
`it had a marked subjective effect in hormonally pretreated
`patients.
`
`398
`IN THE TREATMENT OF ADVANCED PROSTATE CANCER.
`FLUTAMIDE
`Michael A. Keating*, Pamela P. Griffin*, Stephen F. Schiff*
`Boston, MA.(Presentation to be made by Dr. Keating)
`A twelve year experience with the oral non-steroidal
`anti—androgen Flutamide (750 mg qd) allows an assessment of
`its efficacy as therapy for advanced prostatic carcinoma.
`0f 80 patients entered in an open study, 69 were evaluable.
`Of these, 53% (37) achieved complete remission (CR)
`demonstrating total subjective response, normal serum acid
`phosphatase (SAP), cessation of hydronephrosis and improved
`or stable bone surveys. Partial remission (PR) showing
`subjective responses without normalized objective parameters
`occurred in 232 (16) patients. Failure of therapy was seen
`in another 16 patients.
`The average duration of response
`until progression of disease was 28.9 mos. for CR and 12.8
`mos. for PR. Correlation of treatment and tumor grade
`showed CR in 43% (19/44) poorly differentiated, 68% (13/19)
`moderately differentiated and 100% (5/5) well differentiated
`primaries.
`Tumor burden (as a function of T stage, SAP, and
`bone surveys) also correlated with response showing CR in
`222 (7/31) of severely, 687. (17/25) moderately and 100%
`(13/13) mildly afflicted patients. Flutamide was used as an
`alternative to diethylstilbesterol (DES)
`in 10 patients
`actively responding to DES but unable to tolerate its side
`effects.
`A continuation of CR (avg. 33.6 mos.) was seen in
`all 10 cases.
`of another 7 patients failing DES, only I
`achieved CR. Significantly, libido was preserved in 80%
`(29/36) of instances. Other side effects noted were
`gynecomastia 68% (47), altered liver function (3),
`methemoglobulinemia (2) and emesis (2). One death from
`hepatic failure occurred. These findings suggest Flutamide
`may be an effective alternative to conventional hormonal
`therapy in the primary treatment of advanced prostatic
`carcinoma and has encouraged a randomized, prospective
`study presently underway.
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`399
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`COMBINED TREATMENT WITH FLU‘l‘AMIDE IN ASSOCIATION
`WITH MEDICAL 0R SURGICAL CASTRATION.
`F. Labrie,
`A. Dupont, Y. Lacourciere, M. Giguere,
`A. Belanger, G. Monfette and J. Emond
`One hundred and nineteen previously untreated patients
`having clinical stage D prostate cancer received the can-
`bined treatment with the non-steroidal antiandrogen Fluta—
`mide in association with orchiectomy (13 patients) or the
`LHRH agonist
`(D-Trp6) LHRH ethylamide (106 patients). The
`duration of treatment is 515 days (100 to 1156 days). A
`positive objective response assess according to the cri—
`teria of the US National Prostatic Cancer Project has been
`observed in 115 out of 119 patients (96.6%) . Pain was
`initially present in 64% of patients and disappeared in all
`of them during the first month of treatment.
`Serum pro-
`static acid phosphatase was elevated in 85% of cases and
`returned to normal in 95% of cases. Complete, partial and
`stable responses have been obtained in 29 (24%) , 45 (37.8%)
`and 41 (34.5%) of patients, respectively. Of the 15
`(5%)
`deaths, 9 (7.6%) were due to prostate cancer while 6
`resulted frcm other causes. The probability of positive
`response after two years of treatment (according to
`Kaplan and Meier)
`is 60% while the probability of survival
`at the same time interval is 8895. This probability of
`survival should be compared to the rate of 40 to 60% ob-
`served with treat'ments limited to inhibition of testicular
`androgen secretion or action (by surgical or medical
`castration). The present data show that the canbined
`treatment in stage D2 prostate cancer shows advantages as
`compared to previous therapies.
`In terms of percentage of
`positive objective response at the start of treatment,
`duration of remission, survival and quality of life. The
`death rate is in fact decreased by 300% during the first
`two years of treatment while the side effects are limited
`to hot flashes and a decrease or loss of libido.
`It is
`most important to start the administration of the antian-
`drogen at the same time as surgical or medical castration.
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`203A
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