Constellation Pharmaceuticals Presents Results from Phase 1b Portion of ProSTAR Clinical Trial of CPI-1205 at AACR Meeting
- Clinical activity of CPI-1205 was seen in subsets of advanced metastatic castration-resistant prostate cancer (mCRPC) patients
- Recently initiated Phase 2 portion of ProSTAR includes randomized testing of CPI-1205 in combination with enzalutamide versus enzalutamide alone, as well as CPI-1205 in combination with abiraterone
- Initial update from Phase 2 portion of ProSTAR expected in second half of 2019
“We are pleased to report the ProSTAR Phase 1b results,” said
The poster presentation included the following highlights from the Phase 1b portion of ProSTAR, using a
- The Phase 1b portion of ProSTAR enrolled 36 patients: 20 in the CPI-1205 + abiraterone arm and 16 in the CPI-1205 + enzalutamide arm.
- Each arm studied two different dose regimens of CPI-1205 as part of the combination: 800 mg three times daily or 400 mg twice daily + cobicistat (to block CYP3A4).
- The Phase 1b portion of ProSTAR was conducted in a heterogeneous patient population who had been treated with a variety of treatment regimens, including chemotherapy. As such, a significant proportion of patients had indicators of poor prognosis at baseline. Of the 36 patients enrolled, 13 (36%) were positive for Androgen Receptor Splice Variant 7, or AR-V7, isoforms (proteins with similar structures); 20 (56%) had unfavorable circulating tumor cell counts; 13 (36%) had previously received chemotherapy; and 18 (50%) had abnormal levels of lactate dehydrogenase (an enzyme in the blood that can indicate tissue damage, cancer, or some noncancerous conditions) at baseline.
Because patients without AR-V7 isoforms have tended to respond better to ARS inhibition than those with AR-V7 isoforms, and given the hypothesis that ARS inhibition acts synergistically with EZH2 inhibition, patients without AR-V7 isoforms may be more likely to benefit from the potential synergistic effect of CPI-1205 with ARS inhibitor therapy.
- Clinical activity was observed in both the enzalutamide and abiraterone arms, including ≥50%
PSAreductions and an objective response by RECIST 1.1 criteria.
PSAresponses seen in the trial were ≥80%, deeper than the ≥50% reduction endpoint in the trial. All PSAresponses were found in AR-V7-negative patients. Two out of 18 patients in the abiraterone arm achieved PSAreductions of more than 80%. Patients being treated with abiraterone after enzalutamide historically have been shown to achieve poor PSAresponses and rapid time to disease progression. PSAresponses are summarized below:
|≥80% PSA Reductions in AR-V7-Positive Patients||≥80% PSA Reductions in AR-V7-Negative Patients|
|CPI-1205 + abiraterone**||0/8* (0%)||2/10* (20%)|
|CPI-1205 + enzalutamide**||0/5 (0%)||3/11 (27%)|
|*2 patients not evaluable for PSA response|
|** Includes patients treated with CPI-1205 800 mg three times daily and CPI-1205 400mg twice daily + cobicistat|
- The majority of patients with measurable lesions achieved durable disease control during the study, as follows:
|Partial Response||Stable Disease||Disease Control Rate of Any Duration||Disease Control Rate ≥3 Months|
|CPI-1205 + abiraterone||0/8 (0%)||6/8 (75%)||6/8 (75%)||4/8 (50%)|
|CPI-1205 + enzalutamide||1/5 (20%)||2/5 (40%)||3/5 (60%)||3/5 (60%)|
Several patients achieved disease control that exceeded or was approaching six months at the data cutoff while continuing therapy.
- CPI-1205 was generally well tolerated in combination with enzalutamide or abiraterone. The most common treatment-related adverse events (≥20%) were fatigue, diarrhea, and nausea, which were usually mild to moderate in severity and manageable with supportive care. In combination with enzalutamide, treatment-related adverse events ≥ Grade 3 included fatigue, nausea, and increased ALT (n=1; 6.3%, respectively). In combination with abiraterone, treatment-related adverse events ≥ Grade 3 included fatigue and increased ALT (n=1; 5%, respectively). For more details, please see the poster here.
- Patients in two treatment arms were dosed with 800 mg of CPI-1205 three times daily with enzalutamide or abiraterone. Patients in the other two arms were dosed with 400 mg of CPI-1205 twice daily in combination with cobicistat, a CYP3A4 inhibitor, and enzalutamide or abiraterone. While the Company observed in the trial that cobicistat increased the exposure of CPI-1205, the Company did not observe meaningful differences in pharmacodynamics or efficacy compared to 800 mg of CPI-1205 three times daily without cobicistat. Therefore the recommended Phase 2 dose of CPI-1205 for ProSTAR Phase 2 was determined to be 800 mg three times daily.
- The Phase 1b portion of ProSTAR was designed primarily to study the safety, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and a recommended Phase 2 dose of CPI-1205 with abiraterone and enzalutamide. Based on the Phase 1b data, the Company initiated the Phase 2 portion of ProSTAR in late 2018. The Phase 2 portion of the trial is evaluating CPI-1205 in combination with an ARS inhibitor as a second-line treatment for patients with mCRPC. The Company will collect and analyze biomarker and other translational data in Phase 2 to better define which patients may be most likely to respond to treatment with CPI-1205. Two randomized arms of Phase 2 are studying CPI-1205 in combination with enzalutamide versus enzalutamide alone.
In addition, because of the activity seen in the abiraterone arm in the Phase 1b portion of ProSTAR, the Company has also initiated a Phase 2 arm to evaluate CPI-1205 in combination with abiraterone in second-line mCRPC patients. According to a recent study by the laboratory of Dr.
Kim Chiof the Vancouver Prostate Centre, few patients responded to treatment with abiraterone after experiencing disease progression on enzalutamide. For this reason, we have not instituted an additional control arm. In the Chi study, out of 101 patients receiving abiraterone after experiencing disease progression on enzalutamide, no patients achieved an 80% reduction in PSAlevels and only 4% achieved a 50% PSAreduction.1 The patient population in the Chi study had baseline characteristics that are different from those in the Phase 1b portion of ProSTAR, and more similar to those that are expected to be in ProSTAR Phase 2. For example, unlike ProSTAR Phase 1b, in which patients had been previously treated with a range of therapies – including 36% who had received chemotherapy – ProSTAR Phase 2, like the Chi study, is enrolling only patients receiving second-line therapy with no prior chemotherapy in order to focus on activity in that patient population.
- The Company expects to provide an initial update from the Phase 2 portion of ProSTAR in the second half of 2019.
For more information on the Phase 1b portion of ProSTAR, please see the poster here.
1 D Khalaf et al., Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCRPC): results for 2nd-line therapy, poster presented at 2018
Constellation is presenting two additional posters at the
ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205, a potent and highly selective small-molecule EZH2 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) in the second-line setting. The ProSTAR study is evaluating CPI-1205 in combination with either enzalutamide or abiraterone / prednisone (“abiraterone”), which are androgen receptor signaling (ARS) inhibitors, in mCRPC patients who experienced disease progression while receiving the other ARS inhibitor.
Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer and is defined by disease progression despite treatment with androgen depletion therapy (ADT). mCRPC may present as one or any combination of the following: a continuous rise in serum levels of
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MacDougall Biomedical Communications
Source: Constellation Pharmaceuticals