On November 25, 2021 Starpharma (ASX: SPL, OTCQX: SPHRY) reported positive interim results from its ongoing phase 2 trial of DEP cabazitaxel, showing that 100% (22/22) of evaluable[3] patients with hormone refractory, (Stage IV) metastatic prostate cancer (Press release, Starpharma, NOV 25, 2021, View Source;mc_eid=bf52dd3418 [SID1234596084]). All of these patients have been heavily pre-treated and have had efficacy responses, utilising one or more standard measures of disease.
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These interim results in prostate cancer show that one or more encouraging efficacy signals were observed in 100% of patients assessed following DEP cabazitaxel treatment, and 56% of patients who were evaluable for all three efficacy measures had responses to all three measures noted below. Responses included:
64% of patients with assessable tumour lesions saw prolonged stable disease and significant reductions in tumour size for up to 36 weeks with some patients still receiving treatment
90% of patients with assessable PSA (Prostate Specific Antigen) tumour biomarker levels had a reduction in PSA, with more than half of these patients achieving a reduction in PSA of at least 50%
83% of patients with secondary bone disease exhibited either no progression or an improvement in these lesions
These efficacy results are very encouraging, especially given that the prostate cancer patients enrolled in the study were very heavily pre-treated, each having received an average of four prior cancer treatment regimens and an average of more than 70 cycles/months of prior anti-cancer treatment, in addition to surgeries and radiotherapy. Many had also already received marketed taxane chemotherapies, including up to 14 cycles of Taxotere (docetaxel) and 10 cycles of Jevtana (conventional cabazitaxel). One patient had 10 prior treatment regimens, and almost half of the patients had received more than 90 cycles/months of therapy prior to DEP cabazitaxel treatment.
Professor Anthony Joshua, Study Investigator from the Kinghorn Cancer Centre in Sydney with a focus in prostate cancer commented:
"The trial results to date for DEP cabazitaxel in heavily pre-treated prostate cancer patients are highly encouraging and indicate the potential of the product compared to standard cabazitaxel. The anti-cancer activity, together with less myelosuppression than standard cabazitaxel and a generally well-tolerated safety profile, mean this novel form of dendrimer-enhanced cabazitaxel represents a useful option for prostate cancer patients, including in older patients in whom DEP cabazitaxel has been particularly well tolerated."
Efficacy in the prostate cancer cohort in the trial was assessed referencing the applicable aspects of the internationally recognised Prostate Cancer Working Group (PCWG3)[4] guidelines. These guidelines recommend assessing multiple measures of disease control separately, including stable or reduced tumour lesion size, reduced levels of PSA, and/or lack of secondary bone disease progression.[5] Other applicable efficacy measures, such as time to progression (TTP), will be analysed when the ongoing prostate cancer patients have completed treatment in the study.
Patients treated with DEP cabazitaxel also experienced significantly less severe bone marrow toxicity (myelosuppression), significantly lower rates of severe neutropenia and no instances of neutropenic sepsis, which are all significant risks associated with conventional cabazitaxel (Jevtana). Further, the absence of detergent-like polysorbate 80[6] in the DEP cabazitaxel formulation eliminated the need for prophylactic corticosteroids and antihistamines, with no anaphylaxis or severe hypersensitivity reactions observed.
Commenting on the results, Starpharma CEO, Dr Jackie Fairley, said,
"These positive results for DEP cabazitaxel in Stage IV prostate cancer patients are really exciting news for Starpharma and our DEP platform. They include high rates of efficacy across three measures of disease – tumour size, PSA, and bone metastases, and compare favourably with published data for conventional cabazitaxel, e.g., Jevtana, particularly given the heavily pre-treated status of the patients in this trial and their older average age. These highly encouraging results include responses in patients who had previously received taxanes."
Data from this cohort of prostate cancer patients is being presented in confidential commercial discussions with several potential pharmaceutical companies / partners.
A total of 51 patients have now been recruited across all cancer types in the phase 2 DEP cabazitaxel trial. These results reported today relate only to the prostate cancer patients. Recruitment of a small number of additional patients with other tumour types including heavily pre-treated ovarian and gastro-oesophageal cancer patients continues following promising efficacy signals in these tumours. Full results for the trial will be reported separately in the coming months.
The phase 2 DEP cabazitaxel trial is being conducted at multiple sites, including Guy’s Hospital in London, University College London, the Velindre Cancer Centre in Cardiff, Imperial College London, and the Kinghorn Cancer Centre in Sydney.
Interim results for the prostate cancer cohort in the phase 2 DEP cabazitaxel trial
Of the 25 enrolled patients with prostate cancer, 22 were evaluable[7]. All patients enrolled had advanced metastatic (Stage IV) castrate-resistant/hormone refractory prostate cancer. Of these, 14 had soft tissue (non-bone) tumours, 21 had elevated and increasing levels of PSA, and 18 patients had secondary tumours in their bones, or "bone disease".
Of the patients with soft tissue prostate tumours, 64.3% (9/14) achieved prolonged disease control (stable or reduced tumour lesion size) for periods, to date, of up to 36 weeks, following treatment with DEP cabazitaxel. Despite the heavily pre-treated status of the patients in the study, and the advanced stage of their disease, DEP cabazitaxel achieved partial responses"[8] of up to 45% tumour size reduction compared with baseline, in 18.2% (2/11) of patients with measurable disease. This compares favourably with the published clinical study evaluating conventional cabazitaxel (Jevtana) at the same dose (20 mg/m2) where 18.5% of patients dosed with the equivalent amount of cabazitaxel achieved a partial response.[9]
A total of 90.5% (19/21) of patients who had elevated PSA and received DEP cabazitaxel had a reduction in their PSA level, and 52.4% of these patients (11/21) have had a reduction of greater than 50% from baseline to date (noting some patients are still continuing treatment). This result compares very favourably with clinical studies of Jevtana at the same dose as DEP cabazitaxel, in which PSA reduction of >50% occurred in only 29.5% of patients.9
Of the patients with bone disease (secondary tumour in their bones), 83.3% (15/18) exhibited either no progression or an improvement in these lesions after commencing treatment with DEP cabazitaxel.
Nine patients were evaluable for all three efficacy measures and 56% achieved efficacy signals in all three measures.
These very encouraging efficacy findings across multiple measures (tumour size, PSA and bone progression) are particularly impressive given patients in the trial were very heavily pre-treated with multiple prior cancer therapies and had few treatment options. Their disease had progressed on other treatments prior to enrolment in this study. Prostate cancer patients in the study had each received numerous prior treatment cycles with an average of 4 cancer treatment regimens. Prior anti-cancer therapies for the DEP cabazitaxel patients included chemotherapy, immuno-oncology agents, hormonal therapies, radiopharmaceuticals, and targeted therapies, in addition to prior surgeries and radiotherapy.
All but one of the prostate cancer patients treated with DEP cabazitaxel had been previously treated with marketed taxane chemotherapies, including up to 14 cycles of Taxotere (docetaxel) and 10 cycles of Jevtana (cabazitaxel). Compared with published data for Jevtana, prostate cancer patients treated with DEP cabazitaxel were approximately 6 times more likely to have received 3 or more cycles of chemotherapy prior to study entry, and more than 3 times more likely to have received 2 or more cycles. Typically, heavy pre-treatment is associated with a lower treatment response rate.
Unlike Jevtana treated prostate cancer patients, DEP cabazitaxel did not require daily treatment with oral corticosteroids. This avoidance of long-term steroid use is attractive, particularly in prostate cancer patients where bone health can be a significant issue.
Five of the prostate cancer patients remain on treatment in the study with no further enrolment of prostate cancer patients planned. Enrolment continues in other specific tumour types, including ovarian and gastro-oesophageal cancers, where encouraging efficacy signals have also been observed. A number of other patients in the trial with these cancers have achieved significant and sustained reductions in their tumour size (30-53% decrease).
In the trial, treatment with DEP cabazitaxel at 20 mg/m2 cabazitaxel has been well tolerated, and the cohort of prostate cancer patients has received up to 11 cycles. Unlike the marketed form of cabazitaxel, DEP cabazitaxel does not require pre-treatment with antihistamines and steroids to seek to avoid life-threatening allergic and anaphylactic reactions.
The phase 2 prostate cancer patients treated with DEP cabazitaxel have experienced significantly less bone marrow toxicity, particularly neutropenia, than is reported for Jevtana, despite being on average approximately 5 years older (73 years of age) than those in Jevtana registration clinical trials (average age of 68 years).[10]
In contrast to Jevtana, treatment with DEP cabazitaxel was associated with a notable lack of febrile neutropenia and neutropenic infections (0% DEP cabazitaxel vs 2 – 6% with Jevtana) and grade 3 (severe) or higher neutropenia (16% DEP cabazitaxel vs between 42 – 82% with Jevtana). Febrile neutropenia and neutropenic infections are both life-threatening conditions and are particularly problematic in elderly patients.
Jevtana’s recommendation for many patients >65 years old is to receive prophylaxis with G-CSF (granulocyte colony-stimulating factor) from the first cycle (primary prophylaxis) to prevent severe/life-threatening neutropenia. Despite the higher mean age of DEP cabazitaxel treated prostate cancer patients in this study, there has been no need to give any patients, primary G-CSF prophylaxis, including patients over 65. Furthermore, only two patients in the prostate cancer cohort have required any G-CSF therapy following an event of neutropenia.
In this cohort, DEP cabazitaxel was generally well tolerated with the vast majority of adverse events (AEs) reported were mostly mild (grade 1)/moderate (grade 2). AEs observed with DEP cabazitaxel are all reported with conventional cabazitaxel (Jevtana) treatment. These included fatigue, diarrhoea, nausea, vomiting, constipation, peripheral neuropathy, decreased appetite and decreased weight. Additionally, no cases of anaphylaxis, severe hypersensitivity and hair-loss, all of which occur for Jevtana, were observed with DEP cabazitaxel treatment. Patients treated with conventional cabazitaxel (Jevtana) are routinely pre-treated with corticosteroids and antihistamines to reduce the risk of life-threatening anaphylactic reactions to the excipients (detergents) present in conventional cabazitaxel. Starpharma’s DEP cabazitaxel is water soluble, eliminating the need for steroid and antihistamine pre-treatment and the absence of polysorbate-80 reduces the risk of anaphylactic reactions.
About DEP cabazitaxel
DEP cabazitaxel is a patented, detergent free, nanoparticle version of the cancer drug, Jevtana, and is currently in phase 2. Jevtana is a leading oncology agent used to treat advanced prostate cancer with sales of more than US$600 million in 20202. The current (non-dendrimer) formulation of the product has US Food and Drug Administration (FDA)-mandated ‘black box’ warnings in relation to neutropenia, which is a major dose limiting side effect, and severe hypersensitivity (e.g. anaphylaxis) resulting from the polysorbate-80 detergent excipient used in its formulation.
DEP cabazitaxel is one of Starpharma’s three clinical stage DEP assets being developed internally, alongside DEP docetaxel and DEP irinotecan. Starpharma’s intention is to licence internal DEP assets following clinical proof-of-concept/phase-2. Starpharma also has a number of partnered DEP programs including with Merck & Co., Inc., and also a multiproduct DEP licence with AstraZeneca, which includes the development and commercialisation of AZD0466, a novel Bcl2/xL inhibitor, which is in the clinic.