Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Per Applicant’s amendment to the claims, submitted on 05/08/2026, claims 1, 18, and 30 are amended. Currently, claims 1-6, 8-20, 23-24, and 26-38 are pending in the instant application.
Claim Objections - Withdrawn
Objection to claim 8:
In light of Applicant’s amendment to the claims, the objection is hereby withdrawn. The indicated grammatical error has been corrected.
Claim Rejections - 35 USC § 112 Second Paragraph – Withdrawn
Rejection of claim 30:
In light of Applicant’s amendment to the claims, the rejection is hereby withdrawn. Claim 30 now depends upon claim 28 and now provides proper antecedence.
Claim Rejections - 35 USC § 102 – Withdrawn
Rejections of claims 1-6, 8-9, 11-20, 26-28, and 35-38:
In light of Applicant’s amendment to the claims, the rejections are hereby withdrawn. However, new rejections under 35 USC 103 are necessitated by the amendment to claim 1.
Claim Rejections - 35 USC § 103 – Withdrawn
Rejections of claims 10, 23-24, 29, and 31-34:
In light of Applicant’s amendment to the claims the rejections are hereby withdrawn. However, new rejections under 35 USC 103 are necessitated by the amendment to claim 1.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-6, 8-9, 11-20, 26-28, and 35-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Teply (previously referenced).
Claim 1 recites a method for treating prostate cancer in a subject in need thereof, wherein the method comprises:
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Teply teaches a method of treating prostate cancer by administration of androgen. More specifically, the method of Teply indicates the application of bipolar androgen therapy (BAT) wherein subjects are dosed with 400 mg intramuscular testosterone cypionate on day 1 of an every 28 day cycle, further wherein subjects were assessed for PSA levels at the end of each cycle (page 4)1. For patients who had an initial decrease in PSA, such patients were maintained on BAT until a PSA above baseline was achieved (page 5)2. Teply further indicates that subjects achieving PSA >25% higher than baseline were discontinued from BAT and placed on 28 day washout period to allow testosterone levels to return to castrate range, then were subsequently placed on daily 160 mg enzalutamide (i.e., an antiandrogen) treatment for further 28 day cycles (page 5)3. It is further provided that PSA levels were measured during the sequential treatment with enzalutamide (page 5)4. Essentially, Teply teaches the method of element (II) and its substeps (a), (b), (c), and sub paragraphs (i), (ii), and (iii).
Teply does not explicitly teach:
Sub paragraph (iv) wherein upon PSA progression during the sequential treatment cycle, the sequential treatment is discontinued and the first treatment cycle is restarted
Wherein steps (a)-(c) are repeated for at least two cycles by alternating between the first treatment cycle and the sequential treatment cycle until clinical and/or radiographic progression is observed
However, it would be obvious for a person to arrive at such elements because Teply teaches that antiandrogen resistance is a gained function of mCRPC after enzalutamide treatment, and there would be a reasonable chance of success in treating mCRPC with repeated cycles of sequential BAT and antiandrogen treatment.
The teachings of Teply are directed towards treating prostate cancer. More specifically, mCRPC in patients who have been subjected to enzalutamide treatment and have developed resistance to antiandrogens (pages 2-3)5. It is generally understood from the teachings of Teply that mCRPC cells develop resistance to anti-androgen therapies as an adaptation to enzalutamide treatment. As indicated previously, Teply’s method involves a first treatment of BAT cycles using testosterone cypionate, followed by a washout period, then enzalutamide treatment until study end. Teply’s method indicates that the cycles of BAT are able mitigate the gained anti-androgen resistance of mCRPC cells instigated by prior enzalutamide treatment. Given that the method of Teply ends in a final phase of enzalutamide treatment, it would be obvious to repeat the process as needed, as patients with mCRPC suffer the risk of once again gaining resistance to anti-androgens due to the enzalutamide portion of the treatment. Furthermore, because the teachings of Teply provide a degree of predictability in the function of BAT and sequential enzalutamide treatment in patients suffering from anti-androgen resistant mCRPC, the number of repetitions needed would be obvious as a routine optimization of the treatment (see MPEP2144.05(II)(A)).
In summary, Teply teaches a method of treating anti-androgen resistant mCRPC by subjecting patients to a first phase of BAT cycles followed by sequential enzalutamide administration, wherein said BAT cycles lower cancer cell resistance to anti-androgens thereby allowing enzalutamide to once more be effective in treating the mCRPC, but also teaches that enzalutamide treatment leads to anti-androgen resistance in patients with mCRPC. It would have been prima facie obvious at the time of invention for a person of ordinary skill in the art to modify the method of Teply such that the method could be repeated. There would have been a reasonable expectation that such a repetitious treatment would be successful in treating prostate cancer, and particularly mCRPC having resistance to anti-androgens. Accordingly, the teachings of Teply would at least obviate the method described in element (II) of the instant claim.
Claim 2 further limits the method of claim 1 wherein, for the method of subparagraph (I), the second dose, or optionally the third dose, of an androgen, or a derivative thereof, is administered about 28±5 days after the beginning of the first treatment cycle or, if the third dose is administered, about 28±5 days after the beginning of the second treatment cycle.
As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 3 further limits the method of claim 2 wherein the method further comprises starting administration of the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, at the end of a one-, two-, or three-month androgen treatment cycle.
As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 4 further limits the method of claim 3 wherein the method further comprises administering the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, each for one, two, or three 28 ±5 day treatment cycles.
As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 5 further limits the method of claim 4 wherein the method further comprises discontinuing administration of the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, at a completion of the second treatment cycle, or optionally at a completion of the third treatment cycle, and restarting the first treatment cycle comprising administering to the subject a first dose of an androgen, or a derivative thereof, at a beginning of a first treatment cycle and a second dose, and optionally a third dose, of an androgen, or a derivative thereof, at a predetermined interval during the first treatment cycle, or if the third dose is administered, at a predetermined interval during a second treatment cycle.
As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 6 further limits the method of claim 5 wherein the method further comprises alternating the first treatment cycle and the second treatment cycle, and optionally the third treatment cycle, until a clinical and/or radiographic progression is observed.
As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 8 further limits the method of claim 1 wherein, for subparagraph (II), the method further comprises continuing administration of the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, until PSA progression is observed.
Teply indicates that subjects on enzalutamide treatment who experienced an initial decrease in PSA concentration were allowed to remain on the treatment until a PSA increase over baseline (page 5)6.
Claim 9 further limits the method of claim 8 wherein the method further comprises discontinuing administration of the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, once the subject exhibits PSA progression (≥25% increase in PSA from baseline) and restarting the first treatment cycle.
Teply indicates that enzalutamide treatment was discontinued when patients achieved PSA concentration of more than 25% above baseline.
Claim 10 further limits the method of claim 9 wherein the method further comprises alternating between the first treatment cycle and the second treatment cycle, and optionally the third treatment cycle, with onset of PSA progression until clinical and/or radiographic progression is observed.
Teply does not explicitly teach the method of claim 9 wherein the method comprises alternating between first and second treatment cycles. However, altering the method to alternate between cycles of treatment would be obvious because Teply indicates that BAT resensitizes prostate cancer patients to antiandrogens.
As discussed previously, Teply’s teachings are directed to the administration of testosterone to patients having castration resistant prostate cancer, and subsequently administering enzalutamide in a second set of dosing cycles. Teply explicitly indicates that the subjects being tested and having castration resistant prostate cancer had previously been subject to enzalutamide treatment wherein said subjects had PSA progression while on said treatments (page 4)7. After having been treated with three 28 day cycles of supraphysiological levels of testosterone, Teply had found that patients had been resensitized to enzalutamide when treated in cycles subsequent to the testosterone. Per Teply, prostate cancer which progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy. Given that Teply further indicates that such resistance is at least partially reversible by BAT, it would be obvious to alternate cycles of BAT and enzalutamide therapy to counteract the predictable resistance to antiandrogens which would build up over the course of said enzalutamide therapy. A person of ordinary skill in the art would reasonably expect that such a method of alternating treatment cycles would provide a long term and sustainable treatment for castration resistant prostate cancer while ameliorating the risk of antiandrogen resistance build up.
Claim 11 further limits the method of claim further limits the method of claim 1 wherein the first dose of an androgen, or a derivative thereof, and the second dose of an androgen, or a derivative thereof, and optionally the third dose of an androgen, or a derivative thereof, are each sufficient to achieve a supraphysiological serum concentration of testosterone in the subject.
The instant claim further limits the first, second, and optional third dose recited in subparagraph (I) as an alternate of claim 1. As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 12 further limits the method of claim 11 wherein the supraphysiological serum concentration of testosterone is between about 3 to about 10 times a normal serum concentration of testosterone.
The instant claim further limits the first, second, and optional third dose recited in subparagraph (I) as an alternate of claim 1. As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 13 further limits the method of claim 12 wherein the supraphysiological serum concentration of testosterone is greater than about 1500 ng/dL.
The instant claim further limits the first, second, and optional third dose recited in subparagraph (I) as an alternate of claim 1. As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 14 further limits the method of claim 1 wherein the androgen, or derivative thereof is testosterone cypionate or testosterone enanthate at a dose of about 400 to about 500 mg.
The teachings of Teply indicate the dosing of testosterone cypionate at 400 mg.
Claim 15 further limits the method of claim 1 wherein one or more androgens having a different biological potency are administered to the subject, wherein the first dose of an androgen, or a derivative thereof, and the second dose of an androgen, or a derivative thereof, and optionally a third dose of an androgen, or a derivative thereof, are given at a dose range that achieves a same relative supraphysiologic potency as that achieved with testosterone cypionate or testosterone enanthate a dose of about 400 mg to about 500 mg.
The instant claim further limits the first, second, and optional third dose recited in subparagraph (I) as an alternate of claim 1. As iterated in the rejection of claim 1, the teachings of Teply obviate the method of claim 1 wherein the method comprises subparagraph (II). As the instant claim is directed to a further limiting of subparagraph (I) as an alternate, the instant claim would also be obviated.
Claim 16 further limits the method of claim 1 wherein the method comprises administering the androgen orally, transdermally or by intramuscular injection.
Teply teaches the administration of testosterone cypionate by intramuscular injection.
Claim 17 further limits the method of claim 1 wherein the androgen comprises an ester of testosterone or an ester of dihydrotestosterone.
Teply teaches the administration of testosterone cypionate, which is a testosterone ester.
Claim 18 further limits the method of claim 17 wherein the ester of testosterone or the dihydrotestosterone is selected from cypionate, enanthate, propionate, butyrate, and undecanoate ester of testosterone or dihydrotestosterone.
Teply teaches the administration of testosterone cypionate.
Claim 19 further limits the method of claim 18 wherein the androgen or derivative thereof is testosterone cypionate or testosterone enanthate.
Teply teaches the administration of testosterone cypionate.
Claim 20 further limits the method of claim 1 wherein the one or more antiandrogens is selected from the group consisting of bicalutamide, flutamide, nilutamide, apalutamide, darolutamide, enzalutamide, cyproterone acetate, proxalutamide, cimetidine, and topilutamide, and combinations thereof.
Teply teaches the administration of the antiandrogen enzalutamide.
Claim 23 further limits the method of claim 1 wherein the one or more 23. androgen synthesis inhibitors is selected from the group consisting of a CYP17A1 inhibitor, a CYP11A1 (P450scc) inhibitor, a 5a-Reductase inhibitor, and combinations thereof.
As previously discussed in the 102 rejection of claim 1, Teply obviates the method of subparagraph (II), wherein patients with metastatic castration resistant prostate cancer are treated with BAT, utilizing testosterone cypionate, and subsequent treatment with enzalutamide. Teply does not explicitly teach the administration of an androgen synthesis inhibitor as recited in the instant claim. However, it would be obvious to substitute enzalutamide for a CYP17A1 inhibitor because Teply teaches that enzalutamide and abiraterone have cross resistance.
Firstly, assessing the subjects taking part in the disclosed study, Teply indicates that 13 of 30 subjects had previous therapy with both enzalutamide and abiraterone (a CYP17A1 inhibitor) (page 7)8. Secondly, Teply expressly indicates that previously published subject matter has shown evidence of cross resistance between abiraterone and enzalutamide (page 10)9. Thirdly, Teply explicitly makes the suggestion of combining BAT with second line androgen receptor signaling inhibitors (page 10)10. Given the teachings of Teply, it would be obvious to substitute enzalutamide therapy with therapy using an androgen receptor inhibitor such as abiraterone, as a person of ordinary skill in the art would have the reasonable expectation that subjects suffering from castrate resistant prostate cancer would be susceptible to such treatments after being subjected to BAT.
Claim 24 further limits the method of claim 23 wherein the one or more androgen synthesis inhibitors is selected from the group consisting of abiraterone acetate, ketoconazole, seviteronel, aminoglutethimide, alfatradiol, dutasteride, epristeride, finasteride, and combinations thereof.
As indicated in the 103 rejection of claim 23, Teply obviates the use of CYP17A1 inhibitor abiraterone. Accordingly, the instant claim is rejected for the same obviousness reasons as claim 23.
Claim 26 further limits the method of claim 1 wherein the one or more antiandrogens, one or more androgen synthesis inhibitors, or a combination thereof, are administered at a dosage having a range selected from the group between about 100 to about 200 mg/day, between about 110 to about 190 mg/day, between about 120 to about 180 mg/day, between about 130 to about 170 mg/day, and about 160 mg per day.
Teply teaches the administration of enzalutamide at a daily oral dose of 160 mg.
Claim 27 further limits the method of claim 1 wherein the method further comprises androgen deprivation therapy (ADT).
Teply indicates that subjects were placed on luteinizing hormone-releasing hormone agonist therapy alongside BAT (page 2)11. Luteinizing hormone-releasing hormone agonist therapy would be considered as an ADT.
Claim 28 further limits the method of claim 27 wherein the ADT comprises surgical castration or administering a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist.
Teply indicates that subjects were placed on luteinizing hormone-releasing hormone agonist therapy alongside BAT.
Claim(s) 29-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Teply in view of Shore (previously referenced).
Claim 29 further limits the method of claim 28 wherein the LHRH agonist is selected from the group consisting of leuprolide, goserelin, triptorelin, and histrelin.
As discussed previously, the teachings of Teply obviate a method of claim 28 wherein LHRH agonist is administered alongside BAT. Teply does not explicitly teach wherein the agonist is leuprolide, goserelin, triptorelin, and histrelin. However it would be obvious to use at least leuprolide because Shore teaches that leuprolide is a common LHRH agonist for the treatment of prostate cancer.
Shore teaches the treatment of prostate cancer by leuprolide or relugolix. In the case of leuprolide, Shore indicates that the compound is a standard agent for achieving androgen deprivation for the purpose of treating prostate cancer (page 2187)12. Shore teaches that patients suffering from advanced prostate cancer, and treated with leuprolide were able to attain a sustained castration rate of 88.8% (page 2190)13. Given that the method of Teply explicitly teaches the concurrent dosing of LHRH agonist alongside administration of BAT and subsequent antiandrogen, a person of ordinary skill in the art would have found it prima facie obvious to seek out an effective and common LHRH agonist for use with said method, and would have been motivated to use the teachings of Shore as there would be a reasonable expectation of success in treating prostate cancer.
Claim 30 further limits the method of claim 28 wherein the LHRH antagonist is selected from the group consisting of degarelix and relugolix.
As previously discussed in the rejection of claim 29, Shore teaches the use of relugolix in treating prostate cancer. The instant claim would be considered obvious for the same reasons as claim 29.
Claim(s) 31-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Teply in view of Sharma (previously referenced).
Claim 31 further limits the method of claim 1 wherein the method comprises administering immune checkpoint blockade therapy to the subject if the subject exhibits clinical and/or radiographic progression.
As discussed previously in the 103 rejection of claim 1, Teply teaches a method of treating castration resistant metastatic prostate cancer by administration of testosterone cypionate, and subsequent administration of enzalutamide. Teply does not explicitly teach the administration of immune checkpoint blockade therapy. However the application of such therapy would be obvious per the teachings of Sharma because Sharma teaches the treatment of the same disease using a combination of nivolumab and ipilimumab, and there would be a reasonable expectation that incorporating said combination in the teachings of Teply would yield a successful treatment for prostate cancer.
Sharma teaches the treatment of subjects suffering from metastatic castrate resistant prostate cancer using immune checkpoint therapy comprising the administration of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg. Sharma indicates that checkpoint inhibitors which block either PD-1/PD-L1 (such as nivolumab) or CTLA-4 (such as ipilimumab) provide enhanced T-cell mediated antitumor response (page 489-490)14. The combination of both drugs is further indicated to provide anti-tumor activity in chemotherapy naive and chemotherapy experienced patients with mCRPC (page 496)15, and that there is available room for improvement in said treatment by manipulation of dosing amounts and schedules.
As both the methods of the Teply and Sharma are drawn to the treatment of mCRPC, it would have been prima facie obvious to combine the methods of both and administer immune checkpoint blockade therapy, because there would be a reasonable expectation that that such an addition would provide a synergistic effect to the treatment of Teply by ways of inducing anti-tumor activity.
Claim 32 further limits the method of claim 31 wherein the immune checkpoint blockade therapy comprises administering an anti-PD1/PDL1 antibody or an anti-CLA4 antibody.
Sharma teaches the administration of an anti-PD1/PDL1 antibody (nivolumab) and an anti-CLA4 antibody (ipilimumab).
Claim 33 further limits the method of claim 32 wherein the anti-PD1/PDL1 antibody is selected from the group consisting of pembrolizumab, nivolumab, and atezolizumab.
Sharma teaches the administration of nivolumab.
Claim 34 further limits the method of claim 32 wherein the anti-CLA4 antibody comprises ipilimumab.
Sharma teaches the administration of ipilimumab.
Claim 35 further limits the method of claim 1 wherein the subject has progressive prostate cancer after treatment with abiraterone in combination with androgen deprivation therapy (ADT) as an initial therapy or as a second-line therapy after development of resistance to primary ADT.
Teply indicates that a subset of the patients having mCRPC subjected to treatment in the study were previously treated with abiraterone and enzalutamide therapy, wherein enzalutamide therapy would be considered as a form of ADT (page 7)16.
Claim 36 further limits the method of claim 1 wherein the prostate cancer comprises castration resistant metastatic prostate cancer.
The method of Teply is directed towards the treatment of subjects having mCRPC.
Claim 37 further limits the method of claim 1 wherein the subject is asymptomatic.
Teply indicates that a requirement for patient participation in the treatment was to be asymptomatic or minimally symptomatic from the disease (page 4)17.
Claim 38 further limits the method of claim 1 wherein the subject is symptomatic.
Teply indicates that a requirement for patient participation in the treatment was to be asymptomatic or minimally symptomatic from the disease (page 4).
Conclusion
Claims 1-6, 8-20, 23-24, and 26-38 are rejected.
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/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “After verification of eligibility and informed consent procedures, we treated patients with BAT, consisting of intramuscular testosterone cipionate 400 mg on day 1 of an every 28 day cycle while continuing luteinising hormone-releasing hormone agonist therapy. No stopping point was predefined and therapy could continue indefinitely. We did not modify testosterone doses. We assessed patients at each cycle for toxicity and with standard laboratory measures including complete blood count, comprehensive metabolic panel, and PSA.”
2 “We allowed patients who had an initial decrease in PSA with a subsequent rise of more than 25% from nadir to remain on BAT until a PSA increase over baseline.”
3 “Patients who had a consistent rise of PSA concentration after three cycles stopped BAT if PSA was more than 25% higher than the baseline… Patients discontinuing BAT proceeded to a 28 day washout period to allow testosterone concentrations to return to the castrate range. The PSA concentration after washout was considered baseline for purposes of evaluation of enzalutamide response. Treatment proceeded with oral enzalutamide 160 mg daily, with dose adjustments allowed per the US Food and Drug Administration’s label. During treatment with enzalutamide, we clinically assessed patients at each cycle for toxicity with standard laboratory measures including PSA, and radiographic assessments occurred every three cycles. First response assessment occurred after three cycles, and patients with an increase in PSA concentration of more than 25% above baseline discontinued enzalutamide and completed the study.”
4 “During treatment with enzalutamide, we clinically assessed patients at each cycle for toxicity with standard laboratory measures including PSA, and radiographic assessments occurred every three cycles.”
5 “Clinically, metastatic castration-resistant prostate cancer that has progressed after enzalutamide treatment is minimally responsive to further therapy that inhibits androgen receptor signalling. This resistance is often mediated by a reactivation of the androgen receptor-signalling programme, often through androgen receptor overexpression, gene amplification, mutations, and expression of ligand-independent androgen receptor splice variants.”
6 “Patients with an initial decrease in PSA concentration with a subsequent rise of more than 25% from nadir were allowed to remain on enzalutamide until a PSA increase over baseline.”
7 “For the post-enzalutamide cohort, we included patients aged 18 years or older if they had metastatic castration-resistant prostate cancer (disease progression despite a castrate concentration of testosterone [<50 ng/dL]). Evidence of metastatic disease by CT scan or nuclear medicine bone scan was required, but measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) was not a prerequisite for enrolment. Additionally, men were required to have radiographic or prostate-specific antigen (PSA) progression on enzalutamide, and a continuing PSA concentration rise during the 4 week washout from enzalutamide.”
8 “We accrued 30 eligible patients from Aug 28, 2014, to May 18, 2016 (table 1). All patients had previous enzalutamide therapy and 13 had both previous abiraterone and enzalutamide therapy”
9 ”These data are promising considering published series26–29 have shown evidence of cross-resistance between abiraterone and enzalutamide, with objective responses of 0–11% and progression-free survival of 3–4 months in patients receiving abiraterone or enzalutamide after progressing on the alternate drug.”
10 “Furthermore, our results support the hypothesis that an alternative strategy of therapeutically targeting the androgen receptor with BAT in the setting of progression on second-line androgen receptor-signalling inhibitors might be beneficial to patients.”
11 “Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy.”
12 “Injectable luteinizing hormone–releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect.”
13 “Sustained testosterone suppression below castrate levels (<50 ng per deciliter) from day 29 through 48 weeks was achieved in 96.7% of the patients in the relugolix group (95% confidence interval [CI], 94.9 to 97.9) (Fig. 1A). The leuprolide group had a sustained castration rate of 88.8%”
14 “Similarly, clinical trials of anti-PD-1/PD-L1 monotherapies show limited clinical benefit in patients with prostate cancer, including a recent phase III study of atezolizumab that did not meet its primary OS endpoint (Topalian et al., 2012; Hansen et al., 2018; Antonarakis et al., 2020; Sweeney et al., 2020). Since immune checkpoint inhibitors act by blocking the CTLA-4 or PD-1/PD-L1 inhibitory pathway on T cells, leading to enhanced T-cell-mediated antitumor responses with subsequent clinical benefit, successful treatment strategies require tumor-infiltrating T cells.”
15 “In summary, nivolumab plus ipilimumab showed antitumor activity in chemotherapy-naı¨ve and chemotherapy-experienced patients with mCRPC, with preliminary evidence for potential biomarkers of response. These early data support the rationale for further evaluation of immune-checkpoint inhibitor-based combinations in patients with mCRPC, but questions remain in relation to the optimal dose/schedule.”
16 “We accrued 30 eligible patients from Aug 28, 2014, to May 18, 2016 (table 1). All patients had previous enzalutamide therapy and 13 had both previous abiraterone and enzalutamide therapy.”
17 “We also required patients to be asymptomatic or minimally symptomatic from their disease, and have an Eastern Cooperative Oncology Group performance status of 0–2.”
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