On October 19, 2018 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported the presentation today of updated preliminary results from its ongoing Phase 1 clinical study of DCC-2618, the company’s broad-spectrum KIT and PDGFRα inhibitor, in patients with gastrointestinal stromal tumors (GIST) as a proffered paper presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress in Munich, Germany (Press release, Deciphera Pharmaceuticals, OCT 19, 2018, View Source [SID1234529987]).

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"We are extremely pleased with the preliminary results presented today that we believe demonstrate the potential of DCC-2618 to provide improved, durable clinical benefit for GIST patients from second-line through fourth-line-plus," said Michael D. Taylor, Ph.D., President and Chief Executive Officer of Deciphera. "While the data set is still maturing, we believe the median progression free survival value of 42 weeks observed in second-line GIST patients strongly supports our planned randomized Phase 3 study, INTRIGUE, in second-line GIST patients, which we expect to initiate before the end of the year. In addition, the disease control rate and objective response rate observed with DCC-2618 in second-line GIST patients continues to exceed the values reported in previously published, centrally-read, registrational trials for sunitinib."

The presentation reported preliminary results with a cutoff date of August 31, 2018 that include investigator-assessed median progression free survival (mPFS), objective response rates by best response (ORR) and disease control rates at 3 months (DCR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 across 178 patients receiving DCC-2618 at doses of ≥100mg daily:

Notes: (1) Includes nine unconfirmed responses: 2nd line (n=1), 3rd line (n=3) and ≥4th line (n=5); (2) Does not reflect one PR reported after cutoff date, which would result in an ORR in 2nd line of 21% and an ORR in 2nd line and 3rd line combined of 22%; (3) Excludes five patients due to missing data at the time of data cutoff (n=2), lack of first tumor assessment (n=1), withdrawal of consent prior to first assessment (n=1) and unrelated death at C1D4 prior to first assessment (n=1); (4) 59 of 67 combined 2nd line and 3rd line patients received 150mg once daily; and (5) Censored patients for mPFS were 2nd line (58%), 3rd line (52%), 4th line and 4th line plus (35%) and 2nd and 3rd line (55%).

"The preliminary progression free survival data and objective response rates observed with DCC-2618 are very encouraging across all lines of therapy presented: second-, third-, and fourth-line and beyond," said Suzanne George, M.D., Director of Clinical Research, Center for Sarcoma and Bone Oncology and Senior Physician at the Dana Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. "There is a clear unmet need for effective and well tolerated options for patients with metastatic GIST beyond the first-line."

Highlights from the proffered paper include:

Preliminary Clinical Activity in Second-, Third-, Fourth- and Fourth-Line-Plus GIST Patients Demonstrates the Potential for Durable Clinical Outcomes with DCC-2618

Progression Free Survival (mPFS): The mPFS values observed with DCC-2618 were 42 weeks in second-line patients and 40 weeks in third-line patients. Previously published results for approved therapies from centrally-read registrational trials reported a mPFS for sunitinib of 24 weeks in second-line patients and a mPFS for regorafenib of 21 weeks in third-line patients. In fourth- and fourth-line-plus patients, where there are currently no approved therapies, the observed mPFS with DCC-2618 was 24 weeks. Published studies have reported a mPFS of 4-6 weeks for similarly heavily pre-treated patients who did not receive an active therapy.
Disease Control Rate (DCR): The observed DCRs at three months of 79% in second-line patients and 83% in third-line patients exceed the previously published results for approved therapies from centrally-read registrational trials of 60% for sunitinib in second-line patients and 53% for regorafenib in third-line patients. The DCR observed for DCC-2618 in fourth-line and fourth-line-plus patients was 66%.
Objective Response Rate (ORR): The observed ORRs of 18% in second-line patients and 24% in third-line patients continue to exceed the previously published results for approved therapies from centrally-read registrational trials of 7% for sunitinib in second-line patients and 5% for regorafenib in third-line patients. These values do not include a partial response in one second-line patient that was observed after the cutoff date, which would result in an ORR in second-line patients of 21%. The ORR observed for DCC-2618 in fourth-line and fourth-line-plus patients was 9%.
Prolonged Treatment Duration in GIST Patients Receiving DCC-2618 – Cutoff Date of August 31, 2018

In the second-line cohort, as of the cutoff date, 17 patients received DCC-2618 at doses of ≥100mg daily for >6 months with 65% (11 of 17) of these patients remaining on study.
In the third-line cohort, as of the cutoff date, 20 patients received DCC-2618 at doses of ≥100mg daily for >6 months with 75% (15 of 20) of these patients remaining on study.
In the fourth-line and fourth-line-plus patients, as of the cutoff date, 46 patients received DCC-2618 at doses of ≥100mg daily for >6 months with 74% (34 of 46) of these patients remaining on study.
Updated Safety Data Continue to Demonstrate a Favorable Tolerability Profile for DCC-2618

For 178 GIST patients treated at doses above ≥100mg daily, DCC-2618 was generally well tolerated.
Among the treatment-emergent adverse events (TEAEs) reported by investigators (>10%), regardless of relationship to DCC-2618, the most common were: alopecia (50%), myalgia (44%), fatigue (43%), constipation (34%), hand-foot skin reaction (32%), nausea (30%), decreased appetite (28%), weight decreased (24%), abdominal pain (23%), diarrhea (23%) and lipase increase (23%).
Among the 178 GIST patients treated at doses above ≥100mg daily:
14% (24) patients experienced dose reductions due to TEAE.
11% (19) experienced treatment discontinuations due to TEAE.
A copy of the proffered paper will be available on the Deciphera Pharmaceuticals website in the Science section under "Presentations and Publications" located at www.deciphera.com. A copy of the updated Corporate Presentation will be available on the Deciphera Pharmaceuticals website in the Investor section under "Events and Presentations" located at www.deciphera.com.

About DCC-2618
DCC-2618 is a KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, or GIST, systemic mastocytosis, or SM, and glioblastoma multiforme. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting a broad spectrum of mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST as well as the primary D816V exon 17 mutation involved in SM. DCC-2618 also inhibits primary PDGFRα mutations in exons 12, 14 and 18, including the exon 18 D842V mutation, involved in a subset of GIST.

On October 19, 2018 Sensei Biotherapeutics, Inc., a clinical-stage biopharmaceutical company developing precision immuno-oncology therapies, announced today the results of the Phase 1 clinical trial evaluating the safety and immunogenicity of SNS-301 in patients with biochemically recurrent prostate cancer (BRPC) (Press release, Sensei Biotherapeutics, OCT 19, 2018, View Source [SID1234529986]). Patients in the clinical trial were antigen-positive for human aspartate β-hydroxylase (ASPH), a novel tumor-specific embryonic antigen, and selected using Sensei’s proprietary companion diagnostic. SNS-301, a first-in-class immunotherapy candidate targeting ASPH, is the lead clinical candidate in Sensei’s pipeline of innovative cancer immunotherapies created using Sensei’s SPIRIT platform. Results from the Phase 1 study of SNS-301 will be presented at a Poster Discussion session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress, taking place October 19-23, 2018, in Munich, Germany.

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"The principal outcomes from this study further energize our strategy of pursuing next-generation targets, such as ASPH, combined with visionary bioengineering and precision medicine," said John Celebi, President and Chief Executive Officer of Sensei Biotherapeutics. "Based on these positive results, we plan to initiate a Phase 2 trial for SNS-301 in various hematological malignancies and solid tumors in early 2019. We also plan to accelerate the development of our cell therapy programs targeting ASPH and other novel tumor-specific antigens."

"SNS-301’s strong anti-tumor immune activity was shown through increases in both ASPH-specific CD8+ T-cells and ASPH-specific B-cell responses," said Ildiko Csiki, M.D., Ph.D., Chief Medical Officer of Sensei Biotherapeutics. "Based on these compelling early data showing anti-tumor immune response, coupled with a favorable safety profile, we believe SNS-301 has the potential to benefit patients with ASPH-expressing tumors. In a Phase 2 setting, we plan to focus on head and neck cancer, myelodysplastic syndrome, and additional solid tumor indications."

In the multi-center Phase 1 clinical trial, SNS-301 was administered every 21 days via intradermal injection to BRPC patients using a fixed dose-escalation schema to establish the recommended Phase 2 dose. The clinical trial enrolled 12 patients who were confirmed to express ASPH using Sensei’s proprietary serum-based companion diagnostic test. Patients received between 8 to 23 doses of SNS-301 (with an average of 10 doses per patient) at the three different doses in the study, with the cohort of low-dose patients progressing through to the high dose, and the cohort of mid-dose patients escalating successfully to the high dose.

Data from the Phase 1 trial demonstrated a favorable safety profile, improvements in disease-related parameters, and ASPH-specific immune responses. Highlights of the safety and immunogenicity data presented at ESMO (Free ESMO Whitepaper) include:

At all three dose levels in the Phase 1 trial (2 x 1010, 1 x 1011, 3 x 1011 particles), SNS-301 was well tolerated with a favorable safety profile. No dose-limiting toxicities or grade 4-5 adverse events were observed in the trial.
Eight out of the 12 patients (75%) achieved improvements in PSA doubling time and/or absolute PSA level, leading to decreased PSA velocity and suggesting a disease stabilizing effect of SNS-301.
An average 8-to-10-fold increase in the percentage of ASPH-specific CD8+ T-cells was observed post-treatment, compared to baseline measurements. Peak antigen-specific T-cell levels were observed between 43 and 85 days from initial treatment. All seven patients that were evaluable for immune responses showed increases in ASPH-specific T-cells.
An average 5-to-7-fold increase in the percentage of ASPH-specific B-cell responses was observed post-treatment, compared to baseline measurements. Peak antigen-specific B-cell levels were observed between 64 and 106 days from initial treatment. All 12 patients enrolled had increases in ASPH-specific B-cells.
A strong corresponding increase in anti-ASPH antibody titers across patients correlated with B-cell response and a subsequent reduction in serum-based ASPH was observed.
The recommended Phase 2 dose was identified as the mid-dose (1 x 1011 particles) in the Phase 1 trial based on immunogenicity and PSA results of the three evaluated doses.
Sensei’s planned Phase 2 program will evaluate SNS-301 as monotherapy in hematological malignancies and as combination therapy with checkpoint inhibitors in multiple solid tumors, with clinical trials to be initiated in 2019.

About SNS-301
SNS-301 is a first-in-class cancer immunotherapy targeting human aspartate β-hydroxylase (ASPH), a cell surface enzyme that is normally expressed during embryonic development. Following embryonic development, the protein is no longer expressed in healthy adults. Expression of ASPH is uniquely upregulated in more than 20 different types of cancer and is related to cancer cell growth, cell motility and invasiveness. ASPH signaling occurs through the Notch pathway and expression levels in various tumors are inversely correlated with disease prognosis. SNS-301 is a bio-engineered, inactivated bacteriophage virus expressing a fusion protein of native bacteriophage GPD (Glyceraldehyde-3-phosphate dehydrogenase) protein and a selected domain of ASPH. SNS-301 is designed to overcome immune tolerance and induce robust and durable ASPH-specific humoral and cellular responses. SNS-301 is paired with a companion diagnostic to ensure appropriate patient selection and is delivered easily through an intradermal injection to aid in generating robust immune response.

On October 19, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 antagonists to improve immune cell trafficking to treat cancer and rare disease, reported results from a pilot study of X4P-001-IO in combination with Opdivo (nivolumab) in patients with clear cell renal cell carcinoma (ccRCC) who are non-responsive to the anti-PD-1 checkpoint inhibitor Opdivo alone (Press release, X4 Pharmaceuticals, OCT 19, 2018, View Source [SID1234529985]). The data will be presented at a Poster Discussion session at CThe data from this study demonstrate that the combination with X4P-001-IO and nivolumab has the potential to augment responses in patients who previously received the anti-PD-1 checkpoint inhibitor nivolumab alone," said Toni K. Choueiri, M.D. Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and lead investigator of the study. "This pilot study data requires validation in larger studies as we continue to seek treatments to address the larger population of cancer patients who do not adequately respond to checkpoint inhibitors."

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Results were presented from the nine patients with advanced ccRCC enrolled in the pilot study (as of August 1, 2018) who were non-responsive to single agent Opdivo with either stable or progressive disease. Enrolled patients received X4P-001-IO (400 mg, oral, once daily) and continued to receive standard bi-weekly Opdivo therapy. Median duration of treatment with the combination was 3.7 months (range 1-15 months).

Highlights of the data presented at ESMO (Free ESMO Whitepaper) include:

X4P-001-IO in combination with Opdivo was tolerable in ccRCC patients. The most frequent drug related adverse events were diarrhea, nasal congestion, ALT/AST increase, dry eye, fatigue. No grade 4 or 5 adverse events occurred. All Grade 3/serious adverse events were manageable with appropriate intervention.
Combination therapy with X4P-001-IO and Opdivo exhibited anti-tumor activity in some patients with advanced ccRCC who were previously unresponsive to Opdivo monotherapy.
Four patients who had progressed on prior Opdivo monotherapy had a best response of stable disease with the additional X4P-001-IO to Opdivo treatment.
Of the five patients who were stable on prior Opdivo monotherapy, one had a partial response with combination therapy of X4P-001-IO and Opdivo.
Serum biomarker analyses identified significant early changes in cytokines and chemokines, including CXCL9, a chemoattractant ligand for cytotoxic T cell migration.
"These findings add to our clinical experience with X4P-001-IO and our growing understanding of combining CXCR4 antagonists with other agents, such as checkpoint inhibitors," said Ken Gorelick, M.D., Chief Medical Officer of X4 Pharmaceuticals. "X4 continues to explore the important role that CXCR4 antagonism may play in augmenting anti-tumor response in combination with other cancer therapeutic modalities, and therefore, potentially improve outcomes for cancer patients."

About X4P-001-IO in Cancer
X4P-001-IO is an investigational selective, oral, small molecule antagonist of C-X-C receptor type 4 (CXCR4). CXCR4 is a chemokine receptor present in abundance on certain immune cells and cancer cells and it plays a critical role in immune cell trafficking, infiltration and activation in the tumor microenvironment. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment. X4P-001-IO has the ability to help restore immunity within the tumor microenvironment and has the potential to enhance the anti-tumor activity of approved and emerging oncology agents, such as checkpoint inhibitors and targeted therapies. X4P-001-IO is being investigated in several clinical studies in solid tumors.

On October 19, 2018 Boehringer Ingelheim reported results from GioTag, a real-world retrospective study which examined the impact of first-line Giotrif/Gilotrif (afatinib) followed by osimertinib, in epidermal growth factor receptor mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients with acquired T790M mutations, the most common mechanism of resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) (Press release, Boehringer Ingelheim, OCT 19, 2018, View Source [SID1234529984]). The results showed that the sequential strategy was effective in delaying subsequent chemotherapy treatment and were published today in the journal Future Oncology.

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According to the study, the median time on treatment for sequential afatinib and osimertinib was 27.6 months. In this broad, real-world population, the clinical benefit was consistent across all patient subgroups, with particularly encouraging results seen in those with exon 19 deletion (Del19)-positive disease (median time on treatment 30.3 months) and Asian patients (median time on treatment 46.7 months). Additionally, the 2 year and 2.5 year overall survival (OS) rates were 78.9% and 68.8%, respectively.1

Among the patients included in this study, 15.3% had a poor performance status at the start of afatinib treatment (as defined by ECOG performance status ≥2), ordinarily precluding them from clinical trials.1

While osimertinib is an effective first-line treatment,2 there is a lack of approved subsequent TKI treatment options, and many patients progress to chemotherapy following osimertinib failure.1 The results suggest that the sequential strategy of afatinib and osimertinib might offer sustained clinical benefit to a substantial number of patients, prolonging the chemotherapy-free treatment period.1

"With more targeted treatment options becoming available, it is important to understand the impact of multiple lines of targeted therapies on patient outcomes," said Dr. Maximilian J. Hochmair, Medical Oncologist, Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital and coordinating investigator in the trial. "The results of GioTag show that sequential treatment with afatinib and osimertinib is an attractive strategy in patients with EGFR mutation-positive NSCLC, offering a sustained clinical benefit to a substantial number of patients while – importantly – extending the time patients are kept off chemotherapy."

Dr. Victoria Zazulina, Global Head of Solid Tumour Oncology, Medicine at Boehringer Ingelheim, said, "We saw through a recent global survey published at WCLC that many physicians do not feel they have enough information to make informed treatment decisions on how to make the most of the available targeted treatments for patients with EGFR M+ NSCLC; in the absence of randomised data, real-world evidence may help inform treatment decisions. GioTag is the first global study in EGFR M+ NSCLC looking at the sequencing of targeted therapies as it is used in daily clinical practice. These results will provide more insights on the use of EGFR TKIs, looking beyond first-line to maximise overall longer-term impact of targeted therapies in NSCLC."

Results of a recent global survey of HCPs’ attitudes about sequencing treatments for EGFR M+ NSCLC patients are available here. Full results from the GioTag study will be presented at an upcoming medical conference later this year.

On October 19, 2018 Clovis Oncology, Inc. (NASDAQ: CLVS) reported initial data from its ongoing Phase 2 TRITON2 clinical trial of Rubraca at the ESMO (Free ESMO Whitepaper) 2018 Congress (European Society for Medical Oncology) (Press release, Clovis Oncology, OCT 19, 2018, View Source [SID1234529983]). The data show a 44% confirmed objective response rate (ORR) by investigator assessment in 25 RECIST* /PCWG3** response-evaluable patients with a BRCA1/2 alteration. The median duration of response in these patients has not yet been reached. In addition, a 51% confirmed prostate specific antigen (PSA) response rate was observed in 45 PSA response-evaluable patients with a BRCA1/2 alteration.

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The TRITON2 results were the basis for Breakthrough Therapy designation for Rubraca as a monotherapy treatment of adult patients with BRCA1/2 mutated mCRPC who have received at least one prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy, which was granted on October 2, 2018 by the U.S. Food and Drug Administration (FDA). These data will be highlighted in a poster authored by Dr. Wassim Abida, Medical Oncologist, Memorial Sloan Kettering Cancer Center, and principal investigator for the TRITON2 study. The data have been selected for a poster discussion session that will be led by invited discussant Dr. Joaquin Mateo, of the Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO) on 21 October at 09:15-9:40 CEST.

"Rubraca has previously demonstrated antitumor activity in its approved indications for women with advanced ovarian cancer," said Dr. Abida. "These new data show that Rubraca may also offer a new approach for the treatment of mCRPC associated with BRCA1 and BRCA2 alterations, with the potential to achieve a clinical response in patients with few remaining therapy options."

Patients enrolled in the TRITON2 study had received prior treatment with at least one androgen receptor (AR)-directed therapy and taxane-based chemotherapy and were screened for a deleterious germline or somatic alteration in BRCA1, BRCA2 or one of 13 other pre-specified homologous recombination (HR) genes. Study participants were allocated into three cohorts based on the type of gene alteration and disease status, which was determined by genomic sequencing and RECIST criteria, respectively. Each cohort received 600mg Rubraca twice daily and were grouped based on the following criteria: A) alteration in either BRCA1, BRCA2 or ATM genes, with tumors that can be measured with visceral and/or nodal disease; B) alteration in either BRCA1, BRCA2 or ATM genes, with tumors that cannot be measured with visceral and/or nodal disease, or C) alteration in another HR gene associated with sensitivity to PARP inhibition, with or without measurable disease. The primary study endpoints include confirmed ORR per RECIST/PCWG3 in patients with measurable disease at baseline and PSA response in patients with no measurable disease at baseline. Secondary endpoints include overall survival (OS), clinical benefit rate, and safety and tolerability.1

As of the visit cut-off date of June 29, 2018, 85 patients were treated with Rubraca; the overall median treatment duration was 3.7 (range, 0.5–12.9) months and median follow up was 5.7 (range, 2.6–16.4) months. The median treatment duration in patients with a BRCA1/2 alteration was 4.4 months (range, 0.5-12.0 months). Forty-six patients (54.1%) were evaluable for RECIST/PCWG3 response, including 25 patients with a BRCA1/2 alteration. By investigator-assessed RECIST/PCWG3, the confirmed ORR in patients with a BRCA1/2 alteration treated with Rubraca was 44.0% (11/25). Among the 45 evaluable patients with a BRCA1/2 alteration, 51.1% (23/45) had a confirmed PSA response (95% CI, 35.8–66.3).

Overall, the most common treatment-emergent adverse events (TEAEs) of any grade (CTCAE Grade 1-4) in all patients regardless of causality included asthenia/fatigue (44.7%, or 38/85), nausea (42.4%, or 36/85), anemia/decreased hemoglobin (22.4%, or 19/85) and constipation (28.2%, or 24/85). Five patients (5.9%) discontinued therapy due to a non-progression TEAE. One patient died due to disease progression.1

"We are very encouraged by these initial findings from the TRITON2 study, which demonstrate the potential of Rubraca to treat men with advanced prostate cancer whose disease has progressed after receiving multiple prior lines of therapy," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "PARP inhibitors are now a validated therapeutic class in oncology in multiple tumor types, and these new data underscore the benefit that Rubraca may provide for men with advanced, BRCA-mutant castration-resistant prostate cancer. Having recently received Breakthrough Therapy designation based on these data, we are committed to the rapid development of Rubraca for men with this very difficult-to-treat disease."

The poster discussion session also will include the first presentation of genomic profiling data based on tumor tissue and plasma cfDNA samples from the TRITON clinical program. The poster, authored by Dr. Simon Chowdhury, Consultant Medical Oncologist, Guy’s Hospital & Sarah Cannon Research Institute and co-principal investigator for the TRITON clinical studies, will be included in the same poster discussion session as the TRITON2 data, led by invited discussant Dr. Joaquin Mateo, of the Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO). The poster discussion session takes place on 21 October at 09:15-9:40 CEST.

The data suggest cfDNA detected from plasma can be used to identify deleterious HR gene alterations in a manner that is less invasive than tumor tissue testing. Additionally, due to the invasiveness of tumor tissue sample collection, archival primary prostate samples are often used, and data suggest these samples are not representative of the somatic alterations which emerge in mCRPC.

In the study evaluation, patients’ HR gene alteration status was determined by screening a total of 1,311 tumor and 638 plasma specimens, collected from a total of 1,516 patients to determine eligibility for TRITON2 and TRITON3. There was high concordance (74%) in identifying patients with deleterious BRCA1/2 mutations by both tissue and plasma sample. The results demonstrate that detecting genetic alterations within HR genes using cfDNA sequencing could prove to be a convenient method to identify patients who might be suitable candidates for treatment with Rubraca.2 Approximately 12% of men screened for the TRITON2 study were identified as having a BRCA1/2 alteration by plasma screening.

"Tumor tissue testing relies heavily on archival samples taken when a patient is newly diagnosed but may not capture all the alterations that emerge in patients with metastatic disease," said Dr. Chowdhury. "The screening data demonstrate that there is a high concordance between alterations detected in the tissue and plasma assays. Due to the less invasive nature of obtaining cfDNA through plasma testing, this method may be more suitable for both physicians and patients and may also identify more patients eligible for clinical trials of Rubraca."

Clovis’ Rubraca poster presentations will be available online at clovisoncology.com at 07:30 CEST on Saturday, October 20, 2018.

About the TRITON2 Clinical Study

TRITON2 is an international, multicenter, open-label, Phase 2 study of Rubraca in men with metastatic castration-resistant prostate cancer with BRCA gene alterations (inclusive of germline or somatic), which is also enrolling patients with deleterious alterations of other homologous recombination (HR) repair genes, including ATM. The study is currently enrolling across sites worldwide. For more information, please visit www.tritontrials.com.

About Prostate Cancer

The American Cancer Society estimates that more than 164,000 men in the United States will be diagnosed with prostate cancer in 2018,3 and the GLOBOCAN Cancer Fact Sheets estimate that approximately 345,000 men in Europe were diagnosed with prostate cancer in 2012.4 Castration-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castration-resistant prostate cancer, or mCRPC, is an incurable disease, usually associated with poor prognosis. According to the American Cancer Society, the five-year survival rate for mCRPC is approximately 29%.5 Approximately 12% of mCRPC patients have a deleterious mutation in BRCA1 or BRCA2, according to an article published in the Journal of Clinical Oncology Precision Oncology in 2017.6 These molecular markers may be used to select patients for treatment with a PARP inhibitor.

About Rubraca

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and Europe.

Rubraca EU Authorized Use

Rubraca is licensed for adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

Click here to access the current Summary of Product Characteristics. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

Rubraca U.S. FDA Approved Indications and Important Safety Information

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

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